The present invention relates to amidocarboxylic acid derivatives, or their pharmacologically acceptable salts or their pharmacologically acceptable esters. These compounds have some excellent effects of lowering blood glucose, reducing lipid, ameliorating insulin resistance, alleviating inflammatory diseases, immunoregulation, inhibiting aldose reductase, inhibiting 5-lipoxygenase, suppressing generation of lipid peroxide, activating PPAR (peroxysome proliferator activated receptor) and alleviating osteoporosis.
Furthermore, the present invention relates to a composition containing the above-mentioned amidocarboxylic acid derivatives, pharmacologically acceptable salts thereof or pharmacologically acceptable esters thereof as an active ingredient useful in the treatment and prevention of the following diseases. They include diseases caused mainly by insulin resistance such as diabetes mellitus, hyperlipemia, obesity, impaired glucose tolerance (IGT), insulin resistant non-IGT (NGT), hypertension, fatty liver, diabetic complications (for example, retinopathy, nephropathy, neurosis, cataracts, coronary artery diseases, etc.), arteriosclerosis, gestational diabetes mellitus (GDM), polycystic ovary syndrome (PCOS) and cell injury caused by atherosclerosis (for example cerebral injury induced by apoplexy and the like); inflammatory diseases such as arthrosteitis, pain, pyrexia, rheumatic arthritis, inflammatory enteritis, acne, sunburn, psoriasis, eczema, allergic diseases, asthma, GI ulcers, cancer, cachexia, autoimmune diseases and pancreatitis; osteoporosis; cataracts; etc. The present invention relates to a use of these compounds, their salts and esters for producing a medicament for prevention or treatment of these diseases, or a method of treating or preventing these diseases by the administration of pharmacologically effective amounts of such compounds to warm-blooded animals.
While insulin and sulfonylurea compounds such as tolbutamide and Glipizide have conventionally been used as therapeutic agents for diabetes mellitus and hyperglycemia, and carboxylic acid derivatives have recently been reported to be useful insulin-nondependent diabetes therapeutic agents. These compounds are described, for example in:
(1-1) International Patent Publication No. WO91/19702 (Japanese PCT Application (Kokai) No. Hei 5-507920);
(1-2) International Patent Publication WO94/29285;
(1-3) International Patent Publication WO94/29302;
(1-4) International Patent Publication WO95/03288; and
(1-5) International Patent Publication WO96/04260.
However, the compounds described above are different from the compounds of the present invention to be described later in that the former compounds do not have the characteristics of the latter compounds which have an amide bond in the side chain of the carboxylic acid derivative.
Compounds having amide bonds in the side chains are described, for example in:
(2-1) Japanese Patent Application (Kokai) No. Hei 6-172339;
(2-2) International Patent Publication WO 92/07850 (=Japanese PCT Application (Kokai) No. Hei 6-502144); and
(2-3) U.S. Pat. No. 5,330,998.
However, these compounds are different from the compounds of the present invention to be described later in that the former compounds have thiazolidyl groups and the like at the terminal of the molecule.
Although carboxylic acid derivatives having amide bonds in the side chains are described, for example, in:
(3-1) Japanese Patent Application (Kokai) No. Hei 5-155828; and
(3-2) Japanese Patent Application (Kokai) No. Hei 5-279353, the compound (3-1) and the compound (3-2) are different from the present invention in pharmacological activity and chemical structure. The compound (3-1) has an effect of inhibiting aggregation and in the molecule of the compound (3-1) there is an amino group or the like at the 2- to 5-positions of the carboxylic acid and a heterocyclic group or the like at the terminal of the side chain. The compound (3-2) has an inhibitory action against damage of ischemic tissue and is an acetic acid derivative.
The present inventors made intensive studies on amidocarboxylic acid derivatives, and pharmacologically acceptable salts and esters thereof, which have strong effects of lowering blood glucose, reducing lipid, ameliorating insulin resistance, alleviating inflammatory diseases, immunoregulation, inhibiting aldose reductase, inhibiting 5-lipoxygenase, suppressing generation of lipid peroxide, activating PPAR (peroxysome proliferator activated receptor) and alleviating osteoporosis, and accomplished the present invention.
To describe it in detail, the present invention provides novel amidocarboxylic acid derivatives, pharmacologically acceptable salts thereof and pharmacologically acceptable esters thereof which are useful as therapeutic or preventive agents for diseases caused mainly by insulin resistance such as diabetes mellitus, hyperlipemia, obesity, impaired glucose tolerance, insulin resistant non-IGT, hypertension, fatty liver, diabetic complications (e.g., retinopathy, nephropathy, neurosis, cataracts, coronary artery diseases, etc.), arteriosclerosis, gestational diabetes mellitus, polycystic ovary syndrome and cell injury caused by atherosclerosis (for example, cerebral injury induced by apoplexy and the like); inflammatory diseases such as arthrosteitis, pain, pyrexia, rheumatic arthritis, inflammatory enteritis, acne, sunburn, psoriasis, eczema, allergic diseases, asthma, GI ulcers, cancer, cachexia, autoimmune diseases (e.g. systemic lupus erythematosus, juvenile rheumatoid arthritis, Sjogren""s syndrome, diffuse scleroderma, mixed connective tissue disease, dermatomyositis, Hashimoto""s disease, primary myxoma, thyrotoxia, pernicious anemia, ulcerative colitis, autoimmune atrophic gastritis, idiopathic Addison disease, male sterility, Goodpasture""s syndrome, acute progressive glomerulonephritis, myasthenia gravis, polymyositis, pemphigus vulgaris, bullous pemphigoid, sympathetic ophthalmitis, multiple sclerosis, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, rheumatic fever, lupoid hepatitis, primary biliary cirrhosis, Behcet""s disease, CREST syndrome, etc.) and pancreatitis; osteoporosis; and cataracts.
Further, the present invention provides (i) pharmaceutical compositions containing as an active ingredient the novel amidocarboxylic acid derivatives, the pharmacologically acceptable salts thereof or the pharmacologically acceptable esters thereof and (ii) methods of treating by administering said active ingredient to a warm blooded animal, and particularly to a human.
The present invention relates to an amidocarboxylic acid derivative of the formula (I): 
a pharmacologically acceptable salt thereof or a pharmacologically acceptable ester thereof.
In the formula,
R1 represents a hydrogen atom, a straight or branched chain alkyl group having from 1 to 6 carbon atoms or an aralkyl group having from 7 to 12 carbon atoms;
R2 represents a straight or branched chain alkylene group having from 1 to 6 carbon atoms;
R3 represents (i) a hydrogen atom, (ii) a straight or branched chain alkyl group having from 1 to 6 carbon atoms, (iii) a straight or branched chain alkoxy group having from 1 to 4 carbon atoms, (iv) a straight or branched chain alkylthio group having from 1 to 4 carbon atoms, (v) a halogen atom, (vi) a nitro group, (vii) a straight or branched chain dialkylamino group in which each alkyl group may be the same or different and each has from 1 to 4 carbon atoms, (viii) an aryl group having from 6 to 10 carbon atoms which may have from 1 to 5 substituents xcex1 described later, (ix) an aralkyl group having from 7 to 12 carbon atoms which may have from 1 to 5 substituents xcex1 described later on the aryl moiety, (x) a hydroxyl group or (xi) a straight or branched chain aliphatic acyl group having from 1 to 5 carbon atoms;
R4 represents a hydrogen atom or a straight or branched chain alkyl group having from 1 to 6 carbon atoms;
Z represents a straight or branched chain alkylene group having from 1 to 6 carbon atoms;
W represents (i) a straight or branched chain alkyl group having from 1 to 6 carbon atoms, (ii) a hydroxyl group, (iii) a straight or branched chain alkoxy group having from 1 to 4 carbon atoms, (iv) a straight or branched chain alkylthio group having from 1 to 4 carbon atoms, (v) an aryl group having from 6 to 10 carbon atoms which may have from 1 to 5 substituents xcex1 described later, (vi) an aryloxy group having from 6 to 10 carbon atoms which may have from 1 to 5 substituents xcex1 described later on the aryl moiety, (vii) an arylthio group having from 6 to 10 carbon atoms which may have from 1 to 5 substituents xcex1 described later on the aryl moiety, (viii) an aralkyl group having from 7 to 12 carbon atoms which may have from 1 to 5 substituents xcex1 described later on the aryl moiety, (ix) an aralkyloxy group having from 7 to 12 carbon atoms which may have from 1 to 5 substituents xcex1 described later on the aryl moiety, (x) an aralkylthio group having from 7 to 12 carbon atoms which may have from 1 to 5 substituents xcex1 described later on the aryl moiety, (xi) an aryloxyalkyl group in which the aryl moiety has from 6 to 10 carbon atoms which may have from 1 to 5 substituents xcex1 described later and the alkyl moiety is a straight or branched chain alkyl having from 1 to 4 carbon atoms, (xii) a mono- or dicyclic, 5- to 10-membered hetero aryl group containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, (xiii) a mono- or dicyclic, 5- to 10-membered hetero aryloxy group containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, (xiv) a mono- or dicyclic, 5- to 10-membered hetero arylthio group containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, (xv) a mono- or dicyclic, 5- to 10-membered saturated heterocyclic group containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, (xvi) an amino group, (xvii) a straight or branched chain monoalkylamino group in which the alkyl moiety has from 1 to 4 carbon atoms, (xviii) a straight or branched chain dialkylamino group in which each alkyl group may be the same or different and each has from 1 to 4 carbon atoms, (xix) an N-alkyl-N-arylamino group having a straight or branched chain alkyl group having from 1 to 4 carbon atoms and an aryl group having from 6 to 10 carbon atoms which may have from 1 to 5 substituents xcex1, (xx) an arylamino group having from 6 to 10 carbon atoms which may have from 1 to 5 substituents xcex1 described later on the aryl moiety, (xxi) an aralkylamino group having from 7 to 12 carbon atoms which may have from 1 to 5 substituents xcex1 described later on the aryl moiety or (xxii) an aralkyloxycarbonylamino group having an aralkyl group having from 7 to 12 carbon atoms which may have from 1 to 5 substituents xcex1 described later on the aryl moiety;
X represents an aryl group having from 6 to 10 carbon atoms which may have from 1 to 3 substituents xcex1 described later or a mono- or dicyclic, 5- to 10-membered hetero aryl group having from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom which may have from 1 to 3 substituents xcex1 described later, when W represents (1) a straight or branched chain alkyl group having from 1 to 6 carbon atoms, (2) a hydroxyl group, (3) a straight or branched chain alkoxy group having from 1 to 4 carbon atoms, (4) a straight or branched chain alkylthio group having from 1 to 4 carbon atoms, (5) an aryl group having from 6 to 10 carbon atoms which may have from 1 to 5 substituents xcex1 described later, (6) an aryloxy group having from 6 to 10 carbon atoms which may have from 1 to 5 substituents xcex1 described later on the aryl moiety, (7) an arylthio group having from 6 to 10 carbon atoms which may have from 1 to 5 substituents xcex1 described on the aryl moiety, (8) an aralkyl group having from 7 to 12 carbon atoms which may have from 1 to 5 substituents xcex1 described later on the aryl moiety, (9) an aralkyloxy group having from 7 to 12 carbon atoms which may have from 1 to 5 substituents xcex1 described later on the aryl moiety, (10) an aralkylthio group having from 7 to 12 carbon atoms which may have from 1 to 5 substituents xcex1 described later on the aryl moiety, (11) an aryloxyalkyl group in which the aryl moiety is an aryl group having from 6 to 10 carbon atoms which may have from 1 to 5 substituents at described later and the alkyl moiety is a straight or branched chain alkyl having from 1 to 4 carbon atoms, (12) a mono- or dicyclic, 5- to 10-membered hetero aryl group containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, (13) a mono- or dicyclic, 5- to 10-membered hetero aryloxy group containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, (14) a mono- or dicyclic, 5- to 10-membered hetero arylthio group containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom a nitrogen atom and a sulfur atom or (15) a mono- or dicyclic, 5- to 10-membered saturated heterocyclic group containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, or
X represents an aryl group having from 6 to 10 carbon atoms which may have from 1 to 3 substituents xcex1 described later when W represents (1) an amino group, (2) a straight or branched chain monoalkylamino group in which the alkyl moiety has from 1 to 4 carbon atoms, (3) a straight or branched chain dialkylamino group in which each alkyl group may be the same or different and each has from 1 to 4 carbon atoms, (4) an N-alkyl-N-arylamino group having a straight or branched chain alkyl group having from 1 to 4 carbon atoms and an aryl group having from 6 to 10 carbon atoms which may have from 1 to 5 substituents xcex1, (5) an arylamino group having from 6 to 10 carbon atoms which may have from 1 to 5 substituents xcex1 described later on the aryl moiety, (6) an aralkylamino group having from 7 to 12 carbon atoms which may have from 1 to 5 substituents xcex1 described later on the aryl moiety or (7) an aralkyloxycarbonylamino group having an aralkyl group having from 7 to 12 carbon atoms which may have from 1 to 5 substituents xcex1 described later on the aryl moiety.
The above substituent xcex1 represents a group selected from the group consisting of (i) straight or branched chain alkyl groups having from 1 to 6 carbon atoms, (ii) straight or branched chain halogenated alkyl groups having from 1 to 4 carbon atoms, (iii) hydroxylgroups, (iv) straight or branched chain aliphatic acyloxy groups having from 1 to 5 carbon atoms, (v) straight or branched chain aliphatic acyl groups having from 1 to 5 carbon atoms, (vi) straight or branched chain alkoxy groups having from 1 to 4 carbon atoms, (vii) straight or branched chain halogenated alkoxy groups having from 1 to 4 carbon atoms, (viii) straight or branched chain alkylenedioxy groups having from 1 to 4 carbon atoms, (ix) aralkyloxy groups having from 7 to 12 carbon atoms which may have from 1 to 3 substituents xcex2 described later, (x) straight or branched chain alkylthio groups having from 1 to 4 carbon atoms, (xi) straight or branched chain alkylsulfonyl groups having from 1 to 4 carbon atoms, (xii) halogen atoms, (xiii) nitro groups, (xiv) cyano groups, (xv) amino groups, (xvi) straight or branched chain monoalkylamino groups in which the alkyl moiety has from 1 to 4 carbon atoms. (xvii) straight or branched chain alkoxycarbonylamino groups in which the alkoxy moiety has from 1 to 4 carbon atoms, (xiii) aralkyloxycarbonylamino groups in which the aralkyl moiety has from 7 to 12 carbon atoms, (xix) straight or branched chain dialkylamino groups in which each alkyl group may be the same or different and each has from 1 to 4 carbon atoms, (xx) aralkyl groups having from 7 to 12 carbon atoms which may have from 1 to 3 substituents xcex2 described later on the aryl moiety, (xxi) aryl groups having from 6 to 10 carbon atoms and which may have from 1 to 3 substituents xcex2, which may be the same or different, described later, (xxii) aryloxy groups having from 6 to 10 carbon atoms which may have from 1 to 3 substituents xcex2 described later on the aryl moiety, (xxiii) arylthio groups having from 6 to 10 carbon atoms which may have from 1 to 3 substituents xcex2 described later on the aryl moiety, (xxiv) arylsulfonyl groups having from 6 to 10 carbon atoms which may have from 1 to 3 substituents xcex2 described later on the aryl moiety, (xxv) arylsulfonylamino groups having from 6 to 10 carbon atoms which may have from 1 to 3 substituents xcex2 described later on the aryl moiety (the nitrogen atom of the amino moiety may be substituted with a straight or branched chain alkyl group having from 1 to 6 carbon atoms), (xxvi) a mono- or dicyclic, 5- to 10-membered hetero aryl group containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom which may have from 1 to 3 substituents xcex2 described later, (xxvii) a mono- or dicyclic, 5- to 10-membered hetero aryloxy group containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom which may have from 1 to 3 substituents xcex2 described later, (xxviii) a mono- or dicyclic, 5- to 10-membered hetero arylthio group containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom which may have from 1 to 3 substituents xcex2 described later, (xxix) a mono- or dicyclic, 5- to 10-membered hetero arylsulfonyl group containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom which may have from 1 to 3 substituents xcex2 described later, (xxx) a mono- or dicyclic, 5- to 10-membered hetero arylsulfonylamino group containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom which may have from 1 to 3 substituents xcex2 described later on the hetero aryl moiety (the nitrogen atom of the amino moiety may be substituted with a straight or branched chain alkyl group having from 1 to 6 carbon atoms) and (xxxi) a mono- or dicyclic, 5- to 10-membered saturated heterocyclic group containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom;
The above substituent xcex2 represents (i) a straight or branched chain alkyl group having from 1 to 6 carbon atoms, (ii) a straight or branched chain halogenated alkyl group having from 1 to 4 carbon atoms, (iii) a hydroxyl group, (iv) a straight or branched chain alkoxy group having from 1 to 4 carbon atoms, (v) a straight or branched chain halogenated alkoxy group having from 1 to 4 carbon atoms, (vi) a straight or branched chain alkylenedioxy group having from 1 to 4 carbon atoms, (vii) a straight or branched chain hydroxyalkyl group having from 1 to 4 carbon atoms, (viii) a straight or branched chain aliphatic acyl group having from 1 to 5 carbon atoms, (ix) a halogen atom, (x) a nitro group, (xi) a cyano group, (xii) a carboxyl group, (xiii) an amino group, (xiv) a straight or branched chain monoalkylamino group in which the alkyl moiety has from 1 to 4 carbon atoms, (xv) a straight or branched chain dialkylamino group in which each alkyl moiety may be the same or different and each has from 1 to 4 carbon atoms, (xvi) a straight or branched chain aminoalkyl group having from 1 to 4 carbon atoms, (xvii) a monoalkylaminoalkyl group in which the monoalkylamino moiety has one straight or branched chain alkyl group having from 1 to 4 carbon atoms and the alkyl moiety is a straight or branched chain alkyl group having from 1 to 4 carbon atoms, (xviii) a dialkylaminoalkyl group in which the dialkylamino moiety has two straight or branched chain alkyl groups which may be the same or different and each has from 1 to 4 carbon atoms and the alkyl moiety is a straight or branched chain alkyl group having from 1 to 4 carbon atoms, (xix) a straight or branched chain alkoxycarbonylamino group in which the alkoxy moiety has from 1 to 4 carbon atoms or (xx) an aralkyloxycarbonylamino group in which the aralkyl moiety has from 7 to 12 carbon atoms; and
Y represents a single bond, an oxygen atom, a sulfur atom or a group of the formula:  greater than Nxe2x80x94R5 (wherein R5 represents a hydrogen atom, a straight or branched chain alkyl group having from 1 to 6 carbon atoms, a straight or branched chain aliphatic acyl group having from 1 to 8 carbon atoms or an aromatic acyl group having from 7 to 11 carbon atoms).
In the case where R1, R3, R4, R5 or W represent a straight or branched chain alkyl group having from 1 to 6 carbon atoms, the alkyl group includes, for example, a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl or 1,2,2-trimethylpropyl group; preferably, each of R1, R3, R4 and R5 is a straight or branched chain alkyl group having from 1 to 4 carbon atoms, and W is a straight or branched chain alkyl group having from 2 to 6 carbon atoms; more preferably, each of R1, R3, R4 and R5 is a methyl, ethyl, propyl, isopropyl, butyl or isobutyl group, and W is an ethyl, propyl, isopropyl, butyl, isobutyl or pentyl group. Most preferably, each of R1 and R5 is an alkyl group having one or two carbon atoms (particularly a methyl group), R3 is a methyl, ethyl or isopropyl group (particularly a methyl or isopropyl group), R4 is an alkyl group having one or two carbon atoms (particularly a methyl group), and W is a propyl, butyl or pentyl group (particularly a propyl or butyl group).
In the case where R1 represents an aralkyl group having from 7 to 12 carbon atoms, the aralkyl group is a group in which a straight or branched chain alkyl group having from 1 to 4 carbon atoms is substituted with an aryl group and includes, for example, a benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 6-phenylhexyl, 1-naphthylmethyl or 2-naphthylmethyl group, preferably a benzyl, phenethyl or 3-phenylpropyl-group, more preferably a 3-phenylpropyl group.
In the case where R2 or Z represent a straight or branched chain alkylene group having from 1 to 6 carbon atoms, the alkylene group includes, for example, a methylene, ethylene, methylethylene, ethylethylene, 1,1-dimethylethylene, 1,2-dimethylethylene, trimethylene, 1-methyltrimethylene, 1-ethyltrimethylene, 2-methyltrimethylene, 1,1-dimethyltrimethylene, tetramethylene, pentamethylene or hexamethylene group, preferably R2 is a straight or branched chain alkylene group having from 2 to 5 carbon atoms, more preferably R2 is a straight or branched chain alkylene group having from 2 to 4 carbon atoms, still more preferably R2 is an ethylene, trimethylene or methylethylene group, most preferably R2 is an ethylene group. Preferably, Z is a straight or branched chain alkylene group having from 1 to 4 carbon atoms (for example, a methylene, ethylene, methylethylene, ethylethylene, trimethylene, 1-methyltrimethylene or 2-methyltrimethylene group), more preferably an alkylene group having one or two carbon atoms, most preferably a methylene group.
In the case where R3 or W represents a straight or branched chain alkoxy group having from 1 to 4 carbon atoms, the alkoxy group includes, for example, a methoxy, ethoxy, propoxy, isopropoxy, butoxy, s-butoxy, t-butoxy or isobutoxy group; preferably R3 is an alkoxy group having from 1 to 3 carbon atoms (particularly methoxy, ethoxy or isopropoxy group); more preferably an alkoxy group having one or two carbon atoms (particularly a methoxy group). Preferably, W is an alkoxy group having from 1 to 3 carbon atoms, more preferably an ethoxy group.
In the case where R3 or W represents a straight or branched chain alkylthio group having from 1 to 4 carbon atoms, the alkylthio group includes, for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, s-butylthio, t-butylthio or isobutylthio group; preferably R3 is an alkylthio group having one or two carbon atoms; more preferably a methylthio group. W is preferably an alkylthio group having from 1 to 3 carbon atoms (for example, a methylthio, ethylthio, propylthio or isopropylthiogroup); more preferably a methylthio group.
In the case where R3 represents a halogen atom, the halogen atom includes a fluorine atom, a chlorine atom, a bromine atom or an iodine atom; preferably a fluorine atom, a chlorine atom or a bromine atom; more preferably a fluorine atom or a chlorine atom.
In the case where R3 or W represents a straight or branched chain dialkylamino group in which each alkyl group may be the same or different and each has from 1 to 4 carbon atoms, the dialkylamino group includes, for example, a dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, N-methyl-N-ethylamino or N-ethyl-N-isopropylamino group; preferably a dimethylamino or diethylamino group; more preferably a diethylamino group.
In the case where R3 or W represents an aryl group having from 6 to 10 carbon atoms which may have from 1 to 5 substituents xcex1 described later, the unsubstituted aryl group includes, for example, phenyl or naphthyl group, preferably a phenyl group. The substituted aryl group includes, for example, a methylphenyl, ethylphenyl, propylphenyl, isopropylphenyl, trifluoromethylphenyl, hydroxyphenyl, acetylphenyl, methoxyphenyl, methylenedioxyphenyl, benzyloxyphenyl, methylthiophenyl, methanesulfonylphenyl, fluorophenyl, difluorophenyl, chlorophenyl, dichlorophenyl, nitrophenyl, (dimethylamino)phenyl, benzylphenyl, biphenylyl, phenoxyphenyl, phenylthiophenyl, phenylsulfonylphenyl, (phenylsulfonylamino)phenyl, pyridylphenyl, pyridyloxyphenyl, pyridylthiophenyl, (pyridylsulfonylamino)phenyl, methylnaphthyl, trifluoronaphthyl, hydroxynaphthyl, methoxynaphthyl, fluoronaphthyl, chloronaphthyl or pyridylnaphthyl group; preferably an aryl group having from 6 to 10 carbon atoms which may have from 1 to 3 substituents xcex1 described later; more preferably a methylphenyl, ethylphenyl, isopropylphenyl, methoxyphenyl, methylthiophenyl or chlorophenyl group.
In the case where R3 or W represents an aralkyl group having from 7 to 12 carbon atoms which may have from 1 to 5 substituents xcex1 described later on the aryl moiety, the aralkyl group is a group in which the straight or branched chain alkyl group having from 1 to 4 carbon atoms is substituted with the above aryl group and includes, for example, a benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 6-phenylhexyl, naphthylmethyl, methylbenzyl, trifluoromethylbenzyl, methoxybenzyl, methylenedioxybenzyl, methylthiobenzyl, methanesulfonylbenzyl, fluorobenzyl, chlorobenzyl, 2-(methylphenyl)ethyl, 2-(methoxyphenyl)ethyl, 3-(methylphenyl)propyl, 3-(methoxyphenyl)propyl, 4-(methylphenyl)butyl or 4-(methoxyphenyl)butyl group; preferably R3 is a benzyl or phenethyl group; most preferably a benzyl group. W is preferably an aralkyl group having from 7 to 12 carbon atoms which may have from 1 to 3 substituents xcex1 described later on the aryl moiety; more preferably an aralkyl group having from 7 to 10 carbon atoms (for example, a benzyl, phenethyl, 3-phenylpropyl or 4-phenylbutyl group); most preferably a 3-phenylpropyl or 4-phenylbutyl group (particularly the 3-phenylpropyl group).
In the case where R3 represents a straight or branched chain aliphatic acyl group having from 1 to 5 carbon atoms, the aliphatic acyl group includes, for example, a formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl or pivaloyl group, preferably a formyl, acetyl or pivaloyl group; most preferably a formyl or acetyl group.
In the case where W represents an aryloxy group having from 6 to 10 carbon atoms which may have from 1 to 5 substituents xcex1 described later on the aryl moiety, the unsubstituted aryloxy group includes, for example, a phenoxy or naphthyloxy group; preferably a phenoxy group. The substituted aryloxy group includes, for example, a methylphenoxy, ethylphenoxy, propylphenoxy, isopropylphenoxy, t-butylphenoxy, trifluoromethylphenoxy, methoxyphenoxy, ethoxyphenoxy, isopropoxyphenoxy, trifluoromethoxyphenoxy, methylthiophenoxy, ethylthiophenoxy, cyanophenoxy, formylphenoxy, fluorophenoxy, difluorophenoxy, trifluorophenoxy, pentafluorophenoxy, chlorophenoxy, dichlorophenoxy, trichlorophenoxy, pyridylphenoxy, biphenylyloxy, methanesulfonylphenoxy, methylnaphthyloxy, ethylnaphthyloxy, propylnaphthyloxy, isopropylnaphthyloxy, t-butylnaphthyloxy, trifluoromethylnaphthyloxy, methoxynaphthyloxy, ethoxynaphthyloxy, isopropoxynaphthyloxy, trifluoromethoxynaphthyloxy, methylthionaphthyloxy, ethylthionaphthyloxy, cyanonaphthyloxy, formylnaphthyloxy, fluoronaphthyloxy, difluoronaphthyloxy, trifluoronaphthyloxy, pentafluoronaphthyloxy, chloronaphthyloxy, dichloronaphthyloxy, trichloronaphthyloxy, pyridylnaphthyloxy, biphenylyloxy or methanesulfonylnaphthyloxy group; preferably an aryloxy group having from 6 to 10 carbon atoms which may have from 1 to 3 substituents xcex1 described later on the aryl moiety; more preferably a phenoxy group which may have from 1 to 3 substituents xcex1 described later on the phenyl moiety (particularly a phenoxy group which may have one substituent xcex1 described later on the phenyl moiety); most preferably a methylphenoxy, ethylphenoxy, isopropylphenoxy, t-butylphenoxy, trifluoromethylphenoxy, methoxyphenoxy, ethoxyphenoxy, trifluoromethoxyphenoxy, cyanophenoxy, formylphenoxy, fluorophenoxy, difluorophenoxy, trifluorophenoxy, pentafluorophenoxy, chlorophenoxy, dichlorophenoxy, trichlorophenoxy, pyridylphenoxy or methanesulfonylphenoxy group; still most preferably a methylphenoxy, ethylphenoxy, isopropylphenoxy, t-butylphenoxy, trifluoromethylphenoxy, methoxyphenoxy, ethoxyphenoxy, trifluoromethoxyphenoxy, cyanophenoxy, formylphenoxy, fluorophenoxy, difluorophenoxy, trifluorophenoxy, pentafluorophenoxy, chlorophenoxy, dichlorophenoxy, trichlorophenoxy or methanesulfonylphenoxy group; particularly most preferably a 4-methylphenoxy, 4-isopropylphenoxy, 4-t-butylphenoxy, 4-methoxyphenoxy, 4-trifluoromethoxyphenoxy, 3-fluorophenoxy, 4-fluorophenoxy or 4-chlorophenoxy group.
In the case where W represents an arylthio group having from 6 to 10 carbon atoms which may have from 1 to 5 substituents xcex1 described later on the aryl moiety, the unsubstituted arylthio group includes, for example, a phenylthio or naphthylthio group; preferably a phenylthio group. The substituted arylthio group includes, for example, a methylphenylthio, ethylphenylthio, propylphenylthio, isopropylphenylthio, methoxyphenylthio, ethoxyphenylthio, methylthiophenylthio, ethylthiophenylthio, biphenylylthio, 4-methanesulfonylphenylthio, methylnaphthylthio, ethylnaphthylthio, propylnaphthylthio, isopropylnaphthylthio, methoxynaphthylthio, ethoxynaphthylthio, methylthionaphthylthio, ethylthionaphthylthio or 4-methanesulfonylnaphthylthio group; preferably an arylthio group having 6 to 10 carbon atoms which may have from 1 to 3 substituents xcex1 described later; more preferably a phenylthio group which may have from 1 to 3 substituents xcex1 described later on the phenyl moiety; most preferably a methylphenylthio, isopropylphenylthio or methoxyphenylthio group.
In the case where W represents an aralkyloxy group having from 7 to 12 carbon atoms which may have from 1 to 5 substituents xcex1 described later on the aryl moiety, the unsubstituted aralkyloxy group is a group in which the straight or branched chain alkyloxy group having from 1 to 4 carbon atoms is substituted with the above aryl group and includes, for example, a benzyloxy, phenethyloxy, 3-phenylpropyloxy, 4-phenylbutyloxy, 1-naphthylmethyloxy or 2-naphthylmethyloxy group; preferably an aralkyloxy group having from 7 to 10 carbon atoms; more preferably a benzyloxy or phenethyloxy group (particularly a benzyloxy group). The substituted aralkyloxy group includes, for example, a methylbenzyloxy, methoxybenzyloxy, 2-(methylphenyl)ethoxy, 2-(methoxyphenyl)ethoxy, 3-(methylphenyl)propoxy, 3-(methoxyphenyl)propoxy, 4-(methylphenyl)butoxy or 4-(methoxyphenyl)butoxy group; preferably an aralkyloxy group having from 7 to 12 carbon atoms which may have from 1 to 3 substituents xcex1 described later on the aryl moiety; more preferably a methylbenzyloxy or 2-(methylphenyl)ethoxy group.
In the case where W represents an aralkylthio group having from 7 to 12 carbon atoms in the aryl moiety which may have from 1 to 5 substituents xcex1 described later, the unsubstituted aralkylthio group is a group in which the straight or branched chain alkylthio group having from 1 to 4 carbon atoms is substituted with the above aryl group and includes, for example, a benzylthio, phenethylthio, 3-phenylpropylthio, 4-phenylbutylthio, 1-naphthylmethylthio or 2-naphthylmethylthio group; preferably a benzylthio or phenethylthio group; more preferably a benzylthio group. The substituted aralkylthio group includes, for example, a methylbenzylthio, methoxybenzylthio, 2-(methylphenyl)ethylthio, 2-(methoxyphenyl)ethylthio, 3-(methylphenyl)propylthio, 3-(methoxyphenyl)propylthio, 4-(methylphenyl)butylthio or 4-(methoxyphenyl)butylthio group; preferably an aralkylthio group having from 7 to 12 carbon atoms which may have from 1 to 3 substituents xcex1 described later in the aryl moiety; more preferably a methylbenzylthio or 2-(methylphenyl)ethylthio group.
In the case where W represents an aryloxyalkyl group in which the aryl moiety is an aryl group having from 6 to 10 carbon atoms which may have from 1 to 5 substituents xcex1 described later and the alkyl moiety is a straight or branched chain alkyl group having from 1 to 4 carbon atoms, the aryloxyalkyl group includes, for example, a phenoxymethyl, 2-phenoxyethyl, 3-phenoxypropyl, 4-phenoxybutyl, naphthyloxymethyl, 2-naphthyloxyethyl, 3-naphthyloxypropyl or 4-naphthyloxybutyl group; preferably an aryloxyalkyl group in which the aryl moiety is an aryl group having from 6 to 10 carbon atoms which may have from 1 to 3 substituents xcex1 described later and the alkyl moiety is a straight or branched chain alkyl group having from 1 to 4 carbon atoms; more preferably an aryloxyalkyl group in which the aryl moiety has from 6 to 10 carbon atoms and the alkyl moiety is a straight or branched chain and has from 1 to 4 carbon atoms; still more preferably a phenoxymethyl, 2-phenoxyethyl, 3-phenoxypropyl or 4-phenoxybutyl group; most preferably the 2-phenoxyethyl or 3-phenoxypropyl group particularly a 2-phenoxyethyl group).
In the case where W represents a mono- or dicyclic, 5- to 10-membered hetero aryl group containing 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, the hetero aryl group includes, for example, a furyl, thienyl, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolyl or benzoxazolyl group: preferably a pyrrolyl, imidazolyl, furyl, thienyl or pyridyl group; more preferably a pyrrolyl or imidazolyl group.
In the case where W represents a mono- or dicyclic, 5- to 10-membered hetero aryloxy group containing 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, the hetero aryloxy group includes, for example, a furyloxy, thienyloxy, pyrrolyloxy, azepinyloxy, pyrazolyloxy, imidazolyloxy, oxazolyloxy, isoxazolyloxy, thiazolyloxy, isothiazolyloxy, 1,2,3-oxadiazolyloxy, triazolyloxy, tetrazolyloxy, thiadiazolyloxy, pyranyloxy, pyridyloxy, pyridazinyloxy, pyrimidinyloxy, pyrazinyloxy or benzoxazolyloxy group; preferably a furyloxy, thienyloxy, pyrrolyloxy, imidazolyloxy, thiazolyloxy or pyridyloxy group; more preferably a pyridyloxy group.
In the case where W represents a mono- or dicyclic, 5- to 10-membered hetero arylthio group containing 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, the hetero arylthio group includes, for example, a furylthio, thienylthio, pyrrolylthio, azepinylthio, pyrazolylthio, imidazolylthio, oxazolylthio, isoxazolylthio, thiazolylthio, isothiazolylthio, 1,2,3-oxadiazolylthio, triazolylthio, tetrazolylthio, thiadiazolylthio, pyranylthio, pyridylthio, pyridazinylthio, pyrimidinylthio, pyrazinylthio or benzoxazolylthio group; preferably a furylthio, thienylthio, pyrrolylthio, imidazolylthio, thiazolylthio, pyridylthio or benzoxazolylthio group; more preferably a benzoxazolylthio group.
In the case where W represents a mono- or dicyclic, 5- to 10-membered saturated heterocyclic group containing 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom, the saturated heterocyclic group includes, for example, morpholinyl, thiomorpholinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl or piperazinyl group; preferably a morpholinyl, thiomorpholinyl, pyrrolidinyl, imidazolinyl, piperidyl or piperazinyl group.
In the case where W represents a straight or branched chain monoalkylamino group in which the alkyl moiety has from 1 to 4 carbon atoms, the monoalkylamino group includes, for example, a methylamino, ethylamino, propylamino, isopropylamino, butylamino, s-butylamino, t-butylamino or isobutylamino group; preferably a straight or branched chain monoalkylamino group having from 1 to 3 carbon atoms; more preferably a propylamino group.
In the case where W represents a N-alkyl-N-arylamino group having a straight or branched chain alkyl group having from 1 to 4 carbon atoms and an aryl group having from 6 to 10 carbon atoms which may have from 1 to 5 substituents xcex1 described later, the alkyl moeity of the unsubstituted N-alkyl-N-arylamino group includes, for example, a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl or t-butyl group; preferably a methyl, ethyl, propyl, isopropyl, butyl or isobutyl group; more preferably a methyl or ethyl group. The aryl moiety includes, for example, a phenyl or naphthyl group; preferably a phenyl group. Specific examples of the unsubstituted N-alkyl-N-arylamino group includes, for example, a N-methyl-N-phenylamino, N-ethyl-N-phenylamino, N-propyl-N-phenylamino, N-isopropyl-N-phenylamino, N-butyl-N-phenylamino, N-isobutyl-N-phenylamino or N-methyl-N-naphthylamino group; preferably a N-methyl-N-phenylamino or N-ethyl-N-phenylamino group; more preferably a N-ethyl-N-phenylamino group. The substituted N-alkyl-N-arylamino group includes, for example, a N-methyl-N-(methylphenyl)amino, N-ethyl-N-(methylphenyl)amino, N-methyl-N-(methoxyphenyl)amino or N-ethyl-N-(methoxyphenyl)amino group; preferably a N-methyl-N-(methylphenyl)amino or N-ethyl-N-(methylphenyl)amino group.
In the case where W represents an arylamino group having from 6 to 10 carbon atoms which may have from 1 to 5 substituents xcex1 described later on the aryl moiety, the unsubstituted arylamino group includes, for example, a phenylamino or naphthylamino group; preferably a phenylamino group. The substituted arylamino group includes, for example, a (methylphenyl)amino, (ethylphenyl)amino, (propylphenyl)amino, (isopropylphenyl)amino, (methoxyphenyl)amino, (ethoxyphenyl)amino, (methylthiophenyl)amino, (ethylthiophenyl)amino, biphenylylamino or (methanesulfonylphenyl)amino group; preferably a (methylphenyl)amino, (isopropylphenyl)amino or (methoxyphenyl)amino group.
In the case where W represents an aralkylamino group having from 7 to 12 carbon atoms in the aralkyl moiety in which the aryl moiety may have from 1 to 5 substituents xcex1 described later, the unsubstituted aralkylamino group is a group in which a straight or branched chain alkylamino group having from 1 to 4 carbon atoms is substituted with the above aryl group and includes, for example, a benzylamino, phenethylamino, (3-phenylpropyl)amino, (4-phenylbutyl)amino, (1-naphthylmethyl)amino or (2-naphthylmethyl)amino group; preferably a benzylamino or phenethylamino group; more preferably a benzylamino group. The substituted aralkylamino group includes, for example, a (methylbenzyl)amino, (methoxybenzyl)-amino, [2-(methylphenyl)ethyl]amino, [2-(methoxyphenyl)ethyl]amino, [3-(methylphenyl)propyl]amino, [3-(methoxyphenyl)propyl]amino, [4-(methylphenyl)-butyl]amino or [4-(methoxyphenyl)butyl]amino group; preferably a (methylbenzyl)-amino or [2-(methylphenyl)ethyl]amino group.
In the case where W represents an aralkyloxycarbonylamino group having an aralkyl moiety having from 7 to 12 carbon which may have from 1 to 5 substituents xcex1 described later atoms on the aryl moiety, the group includes, for example, a benzyloxycarbonyl group.
In the case where W represents an amino group, a straight or branched chain monoalkylamino group in which the alkyl moiety has from 1 to 4 carbon atoms, a straight or branched chain dialkylamino group in which each alkyl moiety may be the same or different and each has from 1 to 4 carbon atoms, a N-alkyl-N-arylamino group having a straight or branched chain alkyl moiety having from 1 to 4 carbon atoms and an aryl moiety having from 6 to 10 carbon atoms which may have from 1 to 5 substituents xcex1 described later, an arylamino group having from 6 to 10 carbon atoms in the aryl moiety which may have from 1 to 5 substituents xcex1 described later, or an aralkylamino group having from 7 to 12 carbon atoms in the aralkyl moiety in which the aryl moiety may have from 1 to 5 substituents xcex1 described later, W is preferably: an amino group; a straight or branched chain monoalkylamino group in which the alkyl moiety has from 1 to 4 carbon atoms; a straight or branched chain dialkylamino group in which each alkyl group may be the same or different and each has from 1 to 4 carbon atoms; a N-alkyl-N-arylamino group having a straight or branched chain alkyl moiety having from 1 to 4 carbon atoms and an aryl moeity having from 6 to 10 carbon atoms which may have from 1 to 5 substituents xcex1; or an arylamino group having from 6 to 10 carbon atoms in the aryl moiety which may have from 1 to 5 substituents xcex1 described later.
In the case where R5 represents a straight or branched chain aliphatic acyl group having from 1 to 8 carbon atoms or an aromatic acyl group having from 7 to 11 carbon atoms, the acyl group includes, for example, a formyl, acetyl, propionyl, butyryl, pentanoyl, hexanoyl, heptanoyloctanoyl, benzoyl or p-toluoyl group; preferably a straight or branched chain aliphatic acyl group having from 1 to 8 carbon atoms; more preferably a straight or branched chain aliphatic acyl group having from 2 to 5 carbon atoms; most preferably an acetyl group.
In the case where X represents an aryl group having from 6 to 10 carbon atoms which may have from 1 to 3 substituents xcex1 described later, the unsubstituted aryl group includes, for example, a phenyl or naphthyl group, preferably a phenyl group. In the case where X represents an aryl group which is substituted with from 1 to 3 substituents xcex1 described later, the number of the substituents is preferably one or two, more preferably one.
In the case where X represents a mono- or dicyclic, 5- to 10-membered hetero aryl group containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom which may have from 1 to 3 substituents xcex1 described later, the unsubstituted hetero aryl group comprises a monocyclic system or a dicyclic system. In the case of the dicyclic system, one ring thereof at least is a heterocyclic group. In the case of the dicyclic system, two rings are condensed wherein one ring is a heterocycle and the other is a carbocycle, or both rings are heterocycles. The heterocycle is a 5- or 6-membered ring and contains from 1 to 4 hetero atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. The carbocycle is an aryl group having from 6 to 10 carbon atoms. The monocyclic system is called a monocyclic hetero aryl group and the dicyclic system is called a condensed hetero aryl group. In the case of the ring having four hetero atoms, all of the four hetero atoms are preferably nitrogen atoms and the number of hetero atoms selected from the group consisting of an oxygen atom and a sulfur atom is zero. In the case of the ring having three hetero atoms, preferably three, two or one of the hetero atoms are nitrogen atoms and one or two of the hetero atoms are those selected from the group consisting of an oxygen and a sulfur atom. In the case of the ring having two hetero atoms, preferably two, one or zero of the hetero atoms are nitrogen atoms and zero, one or two of the hetero atoms are those selected from the group consisting of an oxygen atom and a sulfur atom. In the case where X represents a hetero aryl group substituted with from 1 to 3 substituents xcex1 described later, the number of the substituents is preferably one or two, more preferably one.
The unsubstituted monocyclic hetero aryl group includes, for example, a pyrrolyl group such as a 2-pyrrolyl or 3-pyrrolyl group; a furyl group such as a 2-furyl or 3-furyl group; a thienyl group such as a 2-thienyl or 3-thienyl group; a pyridyl group such as a 2-pyridyl, 3-pyridyl or 4-pyridyl group; an imidazolyl group such as a 2-imidazolyl or 4-imidazolyl group; a pyrazolyl group such as a 3-pyrazolyl or 4-pyrazolyl group; an oxazolyl group such as a 2-oxazolyl, 4-oxazolyl or 5-oxazolyl group; an isoxazolyl group such as a 3-isoxazolyl, 4-isoxazolyl or 5-isoxazolyl group; a thiazolyl group such as a 2-thiazolyl, 4-thiazolyl or 5-thiazolyl group; an isothiazolyl group such as a 3-isothiazolyl, 4-isothiazolyl or 5-isothiazolyl group; a triazolyl group such as a 1,2,3-triazol-4-yl, or 1,2,4-triazol-3-yl group; a thiadiazolyl group such as a 1,3,4-thiadiazol-2-yl group; an oxadiazolyl group such as a 1,3,4-oxadiazol-2-yl group; a tetrazolyl group such as a 5-tetrazolyl group; a pyridazinyl group such as a 3-pyridazinyl or 4-pyridazinyl group ; a pyrimidinyl group such as a 2-pyrimidinyl, 4-pyrimidinyl or 5-pyrimidinyl group; a pyrazinyl group; an oxazinyl group such as a 1,4-oxazin-2-yl or 1,4-oxazin-3-yl group; and a thiazinyl group such as a 1,4-thiazin-2-yl or 1,4-thiazin-3-yl group; and the unsubstituted condensed hetero aryl group includes, for example, an indolyl group such as an indol-2-yl, indol-3-yl, indol-4-yl, indol-5-yl, indol-6-yl or indol-7-yl group; an indazolyl group such as an indazol-2-yl, indazol-3-yl, indazol-4-yl, indazol-5-yl, indazol-6-yl or indazol-7-yl group; a benzofuranyl group such as a benzofuran-2-yl, benzofuran-3-yl, benzofuran-4-yl, benzofuran-5-yl, benzofuran-6-yl or benzofuran-7-yl group; a benzothiophenyl group such as a benzothiophen-2-yl, benzothiophen-3-yl, benzothiophen-4-yl, benzothiophen-5-yl, benzothiophen-6-yl or benzothiophen-7-yl group; a benzimidazolyl group such as a benzimidazol-2-yl, benzimidazol-4-yl, benzimidazol-5-yl, benzimidazol-6-yl or benzimidazol-7-yl group; a benzoxazolyl group such as a benzoxazol-2-yl, benzoxazol-4-yl, benzoxazol-5-yl, benzoxazol-6-yl or benzoxazol-7-yl group; a benzothiazolyl group such as a benzothiazol-2-yl, benzothiazol-4-yl, benzothiazol-5-yl, benzothiazol-6-yl or benzothiazol-7-yl group; a quinolyl group such as a 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl or 8-quinolyl group; an isoquinolyl group such as a 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl or 8-isoquinolyl group; a benzoxazinyl group such as a 1,4-benzoxazin-2-yl or 1,4-benzoxazin-3-yl group; a benzothiazinyl group such as a 1,4-benzothiazin-2-yl or 1,4-benzothiazin-3-yl group; a pyrrolo[2,3-b]pyridyl group such as a pyrrolo[2,3-b]pyrid-2-yl or pyrrolo[2,3-b]pyrid-3-yl; a furo[2,3-b]pyridyl group such as a furo[2,3-b]pyrid-2-yl or furo[2,3-b]pyrid-3-yl group; a thieno[2,3-b]pyridyl group such as a thieno[2,3-b]pyrid-2-yl or thieno[2,3-b]pyrid-3-yl group; a naphthylidinyl group such as a 1,8-naphthylidin-2-yl, 1,8-naphthylidin-3-yl, 1,5-naphthylidin-2-yl and 1,5-naphthylidin-3-yl group; an imidazopyridyl group such as an imidazo[4,5-b]pyrid-2-yl or imidazo[4,5-b]pyrid-5-yl group; an oxazolopyridyl group such as an oxazolo[4,5-b]pyrid-2-yl or oxazolo[5,4-b]pyrid-2-yl group; and a thiazolopyridyl group such as a thiazolo[4,5-b]pyrid-2-yl or thiazolo[4,5-c]pyrid-2-yl group.
The monocyclic hetero aryl group is preferably a 5- or 6-membered ring group having from 1 to 3 hetero atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom and includes the above-exemplified pyrrolyl group, furyl group, thienyl group, pyridyl group, imidazolyl group, pyrazolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, triazolyl group, thiadiazolyl group, oxadiazolyl group, pyridazinyl group, pyrimidinyl group or pyrazinyl group. The condensed hetero aryl group is preferably a condensed ring group of a benzene ring with the 5- or 6-membered monocyclic hetero aryl group having from 1 to 3 hetero atoms selected from the group consisting of a nitrogen atom, oxygen atom and sulfur atom and includes the above-exemplified indolyl group, benzofuranyl group, benzothiophenyl group, benzimidazolyl group, benzoxazolyl group, benzothiazolyl group, quinolyl group or isoquinolyl group; more preferably an imidazolyl group, oxazolyl group, pyridyl group, indolyl group, quinolyl group or isoquinolyl group; still more preferably a pyridyl group, indolyl group, quinolyl group or isoquinolyl group; and most preferably a pyridyl group, quinolyl group or isoquinolyl group; particularly most preferably a pyridyl group.
In the case where the above group X represents an aryl group having from 6 to 10 carbon atoms or a mono- or dicyclic, 5- to 10-membered hetero aryl group containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, nitrogen atom and sulfur atom, the aryl group and the hetero aryl group may have from 1 to 3 substituents xcex1 as described above.
In the case where the substituent xcex1 represents a straight or branched chain alkyl group having from 1 to 6 carbon atoms, a straight or branched chain alkoxy group having from 1 to 4 carbon atoms, a straight or branched chain alkylthio group having from 1 to 4 carbon atoms, a halogen atom, or a straight or branched chain dialkylamino group in which each alkyl group may be the same or different and each has from 1 to 4 carbon atoms, these groups may include the same groups as described above in the definition of R3. However, in the case where the substituent xcex1 represents a straight or branched chain alkyl group having from 1 to 6 carbon atoms, the alkyl group preferably includes a methyl, ethyl, propyl, isopropyl, butyl or t-butyl, more preferably a methyl, isopropyl or t-butyl group.
In the case where the substituent xcex1 represents an aralkyloxycarbonylamino group in which the aralkyl moiety has from 7 to 12 carbon atoms, the group includes, for example, a benzyloxycarbonylamino group.
In the case where the substituent xcex1 represents a straight or branched chain halogenated alkyl group having from 1 to 4 carbon atoms, the halogenated alkyl group includes, for example, a chloromethyl, bromomethyl, fluoromethyl, iodomethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl or trichloromethyl group; preferably a fluoromethyl having from 1 to 3 fluorine atoms; more preferably a trifluoromethyl.
In the case where the substituent xcex1 represents a straight or branched chain aliphatic acyloxy group having from 1 to 5 carbon atoms, the acyloxy group includes, for example, a formyloxy, acetoxy, propionyloxy, butyryloxy, acroyloxy, methacroyloxy or crotonoyloxy group; preferably an alkanoyloxy group having from 1 to 4 carbon atoms; more preferably an alkanoyloxy group having one or two carbon atoms; most preferably an acetoxy group.
In the case where the substituent xcex1 represents a straight or branched chain halogenated alkoxy group having from 1 to 4 carbon atoms, the halogenated alkoxy group includes, for example, a chloromethoxy, bromomethoxy, fluoromethoxy, iodomethoxy, difluoromethoxy, trifluoromethoxy, pentafluoroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, trichloromethoxy or 2,2,3,3-tetrafluoropropoxy group; preferably a straight or branched chain halogenated alkoxy group having from 1 to 3 carbon atoms; more preferably a methoxy group having from 1 to 3 fluorine atoms or a 2,2,3,3-tetrafluoropropoxy group; most preferably a trifluoromethoxy or 2,2,3,3-tetrafluoropropoxy group (particularly a 2,2,3,3-tetrafluoropropoxy group).
In the case where the substituent xcex1 represents a straight or branched chain aliphatic acyl group having from 1 to 5 carbon atoms, the acyl group includes, for example, a formyl, acetyl, propionyl, butyryl, acroyl, methacroyl or crotonoyl group; preferably a straight or branched chain aliphatic acyl group having 2 or 3 carbon atoms; more preferably an acetyl group.
In the case where the substituent xcex1 represents a straight or branched chain alkylenedioxy group having from 1 to 4 carbon atoms, the alkylenedioxy group includes, for example, a methylenedioxy, ethylenedioxy, trimethylenedioxy, tetramethylenedioxy or propylenedioxy group; preferably a methylenedioxy or ethylenedioxy group; more preferably a methylenedioxy group.
In the case where the substituent xcex1 represents an aralkyloxy group having from 7 to 12 carbon atoms which may have from 1 to 3 substituents xcex2 described later, the aralkyloxy group includes, for example, a benzyloxy, phenethyloxy, 3-phenylpropoxy, 4-phenylbutoxy, 1-naphthylmethoxy or 2-naphthylmethoxy group; preferably an unsubstituted aralkyloxy having from 7 to 12 carbon atoms (for example, a-benzyloxy, 2-phenethyloxy, 1-naphthylmethoxy or 2-naphthylmethoxy group); more preferably a benzyloxy group.
In the case where the substituent xcex1 represents a straight or branched chain alkylsulfonyl group having from 1 to 4 carbon atoms, the alkylsulfonyl group includes, for example, a methanesulfonyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, butanesulfonyl, isobutanesulfonyl, s-butanesulfonyl or t-butanesulfonyl group, preferably a methanesulfonyl, ethanesulfonyl or isopropanesulfonyl group; particularly preferably an alkylsulfonyl group having from one or two carbon atoms (particularly a methanesulfonyl group).
In the case where the substituent xcex1 represents a straight or branched chain monoalkylamino group in which the alkyl moiety has from 1 to 4 carbon atoms, the monoalkylamino group includes, for example, a methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, s-butylamino or t-butylamino group; preferably a methylamino, ethylamino, isopropylamino or t-butylamino group; more preferably a methylamino group.
In the case where the substituent xcex1 represents a straight or branched chain alkoxycarbonylamino group in which the alkoxy moiety has from 1 to 4 carbon atoms, the alkoxycarbonylamino group includes, for example, a methoxycarbonylamino, ethoxycarbonylamino or t-butoxycarbonylamino group; preferably a t-butoxycarbonylamino group.
In the case where the substituent xcex1 represents an aralkyl group having from 7 to 12 carbon atoms in the aryl moiety which may have from 1 to 3 substituents xcex2 described later, the aralkyl group includes, for example, a benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 6-phenylhexyl, 1-naphthylmethoxy or 2-naphthylmethoxy group; preferably a benzyl group which may have from 1 to 3 substituents xcex2 described later on the phenyl moiety; more preferably a benzyl group.
In the case where the substituent xcex1 represents an aryl group having from 6 to 10 carbon atoms which may have from 1 to 3 substituents xcex2, which may be the same or different, described later, the aryl group includes, for example, a phenyl, naphthyl, methylphenyl, (trifluoromethyl)phenyl, hydroxyphenyl, methoxyphenyl, ethoxyphenyl, (trifluoromethoxy)phenyl, methylenedioxyphenyl, (hydroxymethyl)phenyl, fluorophenyl, chlorophenyl, bromophenyl, nitrophenyl, formylphenyl, cyanophenyl, carboxyphenyl, aminophenyl, (dimethylamino)phenyl, (aminomethyl)phenyl, (2-aminoethyl)phenyl, [(N,N-dimethylamino)methyl]phenyl, (t-butoxycarbonylamino)phenyl, (benzyloxycarbonylamino)phenyl or 4-hydroxy-3,5-dimethylphenyl group; preferably a phenyl group which may have from 1 to 3 substituents xcex2 described later (particularly, a phenyl, methylphenyl, (trifluoromethyl)phenyl, hydroxyphenyl, methoxyphenyl, (trifluoromethoxy)phenyl, methylenedioxyphenyl, (hydroxymethyl)phenyl, fluorophenyl, chlorophenyl, nitrophenyl, formylphenyl, cyanophenyl, carboxyphenyl, dimethylaminophenyl, aminomethylphenyl, (N,N-dimethylaminomethyl)phenyl or 4-hydroxy-3,5-dimethylphenyl group); more preferably a phenyl, methylphenyl, (trifluoromethyl)phenyl, hydroxyphenyl, methoxyphenyl, (trifluoromethoxy)phenyl, methylenedioxyphenyl, (hydroxymethyl)phenyl, fluorophenyl, chlorophenyl, nitrophenyl, formylphenyl, cyanophenyl, carboxyphenyl, (dimethylamino)phenyl, (aminomethyl)phenyl, (N,N-dimethylaminomethyl)phenyl or 4-hydroxy-3,5-dimethoxyphenyl group; most preferably a phenyl, (trifluoromethyl)phenyl, methoxyphenyl, (hydroxymethyl)phenyl, (trifluoromethoxy)phenyl, fluorophenyl, fluorophenyl, chlorophenyl, chlorophenyl, nitrophenyl, formylphenyl, carboxyphenyl, dimethylaminophenyl, (N,N-dimethylaminomethyl)phenyl or 4-hydroxy-3,5-dimethylphenyl group; particularly most preferably a phenyl, (trifluoromethoxy)phenyl, methoxyphenyl, fluorophenyl, chlorophenyl, formylphenyl, carboxyphenyl or (dimethylamino)phenyl group.
In the case where the substituent xcex1 represents an aryloxy group having from 6 to 10 carbon atoms in the aryl moiety which may have from 1 to 3 substituents xcex2 described later, the aryloxy group includes, for example, a phenoxy, naphthoxy, methylphenoxy, (trifluoromethyl)phenoxy, methoxyphenoxy, ethoxyphenoxy, fluorophenoxy, chlorophenoxy, bromophenoxy or methylenedioxyphenoxy group; preferably a phenoxy group which may have from 1 to 3 substituents xcex2 described later (particularly a phenoxy group).
In the case where the substituent xcex1 represents an arylthio group having from 6 to 10 carbon atoms in the aryl moiety which may have from 1 to 3 substituents xcex2 described later, the arylthio group includes, for example, a phenylthio, methylphenylthio, (trifluoromethyl)phenylthio, methoxyphenylthio, ethoxyphenylthio, chlorophenylthio, bromophenylthio, methylenedioxyphenylthio or naphthylthio group; preferably a phenylthio group which may have from 1 to 3 substituents xcex2 described later (particularly a phenylthio group).
In the case where the substituent xcex1 represents an arylsulfonyl group having from 6 to 10 carbon atoms in the aryl moiety which may have from 1 to 3 substituents xcex2 described later, the arylsulfonyl group includes, for example, a phenylsulfonyl, methylphenylsulfonyl, (trifluoromethyl)phenylsulfonyl, methoxyphenylsulfonyl, ethoxyphenylsulfonyl, chlorophenylsulfonyl, bromophenylsulfonyl, methylenedioxyphenylsulfonyl or naphthylsulfonyl group; preferably a phenylsulfonyl group which may have from 1 to 3 substituents xcex2 described later.
In the case where the substituent xcex1 represents an arylsulfonylamino group having from 6 to 10 carbon atoms in the aryl moiety which may have from 1 to 3 substituents xcex2 described later (the nitrogen atom of the amino moiety may be substituted with a straight or branched chain alkyl group having from 1 to 6 carbon atoms), the alkyl moiety of the substituent on the nitrogen atom has the same meaning as defined above. The arylsulfonylamino group includes, for example, a (phenylsulfonyl)amino, (methylphenylsulfonyl)amino, (trifluoromethylphenylsulfonyl)amino, (methoxyphenylsulfonyl)amino, (ethoxyphenylsulfonyl)amino, chlorophenylsulfonylamino, bromophenylsulfonylamino, methylenedioxyphenylsulfonylamino, N-methyl-phenylsulfonylamino, (naphthylsulfonyl)amino or N-methyl-naphthylsulfonylamino group; preferably a (phenylsulfonyl)amino group which may have from 1 to 3 substituents xcex2 described later on the phenyl moiety or a N-methyl-phenylsulfonylamino group (particularly a phenylsulfonylamino or N-methyl-phenylsulfonylamino group).
In the case where the substituent xcex1 represents a mono- or dicyclic, 5- to 10-membered hetero aryl group containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, nitrogen atom and sulfur atom which may have from 1 to 3 substituents xcex2 described later, the unsubstituted hetero aryl group includes, for example, a furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, quinolyl, isoquinolyl, indolyl or pyridyl group; preferably an imidazolyl, quinolyl or pyridyl group; particularly preferably a pyridyl group. The group having a substituent includes methylpyridyl, (trifluoromethyl)pyridyl, hydroxypyridyl, methoxypyridyl, ethoxypyridyl, (trifluoromethoxy)pyridyl, (hydroxymethyl)pyridyl, fluoropyridyl, chloropyridyl, bromopyridyl, nitropyridyl, formylpyridyl, cyanopyridyl, carboxypyridyl, aminopyridyl, (dimethylamino)pyridyl, (aminomethyl)pyridyl, (2-aminoethyl)pyridyl, (N,N-dimethylaminomethyl)pyridyl, (t-butoxycarbonylamino)pyridyl or (benzyloxycarbonylamino)pyridyl group; preferably a pyridyl group which may have from 1 to 3 substituents xcex2 described later (for example, a methylpyridyl, (trifluoromethyl)pyridyl, hydroxypyridyl methoxypyridyl, (trifluoromethoxy)pyridyl, fluoropyridyl, chloropyridyl, nitropyridyl, formylpyridyl, cyanopyridyl, carboxypyridyl, aminopyridyl, dimethylaminopyridyl or (N,N-dimethylaminomethyl)pyridyl) group or an imidazolyl group (the nitrogen atom of the ring may be substituted with a straight or branched chain alkyl group having from 1 to 6 carbon atoms, particularly a N-methylimidazolyl group); more preferably a (trifluoromethyl)pyridyl, methoxypyridyl, fluoropyridyl, chloropyridyl, nitropyridyl, cyanopyridyl, aminopyridyl or dimethylaminopyridyl group.
In the case where the substituent xcex1 represents a mono- or dicyclic, 5- to 10-membered hetero aryloxy group containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, nitrogen atom and sulfur atom which may have from 1 to 3 substituents xcex2 described later, the hetero aryloxy group includes, for example, a furyloxy, thienyloxy, oxazolyloxy, isoxazolyloxy, thiazolyloxy, imidazolyloxy, quinolyloxy, isoquinolyloxy, indolyloxy or pyridyloxy group; preferably a pyridyloxy group which may have from 1 to 3 substituents xcex2 described later; particularly preferably a pyridyloxy group.
In the case where the substituent xcex1 represents a mono- or dicyclic, 5- to 10-membered hetero arylthio group containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, nitrogen atom and sulfur atom which may have from 1 to 3 substituents xcex2 described later, the hetero arylthio group includes, for example, a furylthio, thienylthio, oxazolylthio, isoxazolylthio, thiazolylthio, imidazolylthio, quinolylthio, isoquinolylthio, indolylthio or pyridylthio group; preferably a pyridylthio group which may have from 1 to 3 substituents xcex2 described later; particularly preferably a pyridylthiogroup.
In the case where the substituent xcex1 represents a mono- or dicyclic, 5- to 10-membered hetero arylsulfonyl group containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, nitrogen atom and sulfur atom which may have from 1 to 3 substituents xcex2 described later, the hetero arylsulfonyl group includes, for example, a furylsulfonyl, thienylsulfonyl, oxazolylsulfonyl, isoxazolylsulfonyl, thiazolylsulfonyl, imidazolylsulfonyl, quinolylsulfonyl, isoquinolylsulfonyl, indolylsulfonyl or pyridinesulfonyl group; preferably a pyridylsulfonyl group which may have from 1 to 3 substituents xcex2 described later; particularly preferably a pyridylsulfonyl group.
In the case where the substituent xcex1 represents a mono- or dicyclic, 5- to 10-membered hetero arylsulfonylamino group containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, nitrogen atom and sulfur atom which may have from 1 to 3 substituents xcex2 described later in the hetero aryl moiety (the nitrogen atom of the amino moiety may be substituted with a straight or branched chain alkyl group having from 1 to 6 carbon atoms), the hetero arylsulfonylamino group includes, for example, a furylsulfonylamino, thienylsulfonylamino, oxazolylsulfonylamino, isoxazolylsulfonylamino, thiazolylsulfonylamino, imidazolylsulfonylamino, N-methyl-imidazolylsulfonylamino, quinolylsulfonylamino, isoquinolylsulfonylamino, indolylsulfonylamino, pyridylsulfonylamino or N-methylpyridylsulfonylamino group; preferably a pyridylsulfonylamino group which may have from 1 to 3 substituents xcex2 described later on the pyridyl moiety (the nitrogen atom of the amino moiety may be substituted with a straight or branched chain alkyl group having from 1 to 6 carbon atoms); particularly preferably a pyridinesulfonylamino or N-methyl-pyridinesulfonylamino group.
In the case where the substituent xcex1 represents a mono- or dicyclic, 5- to 10-membered saturated heterocyclic group containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, nitrogen atom and sulfur atom, the saturated heterocyclic group includes, for example, a morpholinyl, thiomorpholinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl or piperazinyl group; preferably a morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidyl or piperazinyl group (particularly a piperidyl group).
In the case where the substituent xcex2 represents a straight or branched chain alkyl group having from 1 to 6 carbon atoms, a straight or branched chain alkoxy group having from 1 to 4 carbon atoms, a halogen atom, or a straight or branched chain dialkylamino group in which each alkyl group may be the same or different and each has from 1 to 4 carbon atoms, these groups may include the same groups as described above in the definition of R3.
In the case where the substituent xcex2 represents a straight or branched chain halogenated alkyl group having from 1 to 4 carbon atoms, a straight or branched chain halogenated alkoxy group having from 1 to 4 carbon atoms, a straight or branched chain alkylenedioxy group having from 1 to 4 carbon atoms, a straight or branched chain aliphatic acyl group having from 1 to 5 carbon atoms, a straight or branched chain monoalkylamino group in which the alkyl moiety has from 1 to 4 carbon atoms, a straight or branched chain alkoxycarbonylamino group in which the alkoxy moiety has from 1 to 4 carbon atoms, or an aralkyloxycarbonylamino group in which the aralkyl moiety has from 7 to 12 carbon atoms, these groups may include the same groups as described above in the definition of xcex1.
In the case where the substituent xcex2 represents a straight or branched chain hydroxyalkyl group having from 1 to 4 carbon atoms, the hydroxyalkyl group includes, for example, a hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl or 4-hydroxybutyl group, preferably a hydroxymethyl group.
In the case where the substituent xcex2 represents a straight or branched chain aminoalkyl group having from 1 to 4 carbon atoms, the aminoalkyl group includes, for example, an aminomethyl, 2-aminoethyl, 3-aminopropyl or 4-aminobutyl group; preferably an aminomethyl or aminoethyl group; more preferably an aminomethyl group.
In the case where the substituent xcex2 represents a monoalkylaminoalkyl group in which the monoalkylamino moiety has one straight or branched chain alkyl group having from 1 to 4 carbon atoms and the alkyl moiety is a straight or branched chain alkyl having from 1 to 4 carbon atoms, the monoalkylaminoalkyl group includes, for example, a N-methylaminomethyl, N-ethylaminomethyl, N-methylaminoethyl, N-ethylaminoethyl, N-methylaminopropyl or N-methylaminobutyl group; preferably a N-methylaminomethyl or N-methylaminoethyl group.
In the case where the substituent xcex2 represents a dialkylaminoalkyl group in which the dialkylamino moiety has two straight or branched chain alkyl groups having from 1 to 4 carbon atoms which may be the same or different, and the alkyl moiety is a straight or branched chain alkyl group having from 1 to 4 carbon atoms, the dialkylaminoalkyl group includes, for example, a N,N-dimethylaminomethyl, N,N-diethylaminomethyl, N,N-dimethylaminoethyl, N,N-diethylaminoethyl, N,N-dimethylaminopropyl or N,N-dimethylaminobutyl group; preferably a N,N-dimethylaminomethyl or N,N-dimethylaminoethyl group; more preferably a N,N-dimethylaminomethyl group.
Therefore, in the case where X represents a substituted or unsubstituted aryl group having from 6 to 10 carbon atoms or a substituted or unsubstituted mono- or dicyclic, 5- to 10-membered hetero aryl group containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, nitrogen atom and sulfur atom, specific example of these groups preferably includes a phenyl, 1-naphthyl, 2-naphthyl, m-tolyl, p-tolyl, 3-ethylphenyl, 4-ethylphenyl, 3-isopropylphenyl, 4-isopropylphenyl, 3-t-butylphenyl, 4-t-butylphenyl, 4-chloromethylphenyl, 4-bromomethylphenyl, 4-fluoromethylphenyl, 4-iodomethylphenyl, 3-difluoromethylphenyl, 4-trifluoromethylphenyl, 4-pentafluoroethylphenyl, 4-trichloromethylphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-acetoxyphenyl, 4-acetoxyphenyl, 5-acetoxy-2-hydroxy-3,4,6-trimethylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 3-isopropoxyphenyl, 4-isopropoxyphenyl, 3,4-methylenedioxyphenyl, benzyloxyphenyl, phenethyloxyphenyl, 1-naphthylmethoxyphenyl, 3-methylthiophenyl, 4-methylthiophenyl, 3-ethylthiophenyl, 4-ethylthiophenyl, 3-isopropylthiophenyl, 4-isopropylthiophenyl, 3-methanesulfonylphenyl, 4-methanesulfonylphenyl, 3-ethanesulfonylphenyl, 4-ethanesulfonylphenyl, 3-isopropanesulfonylphenyl, 4-isopropanesulfonylphenyl, 3-fluorophenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-bromophenyl, 4-bromophenyl, 4-nitrophenyl, 4-aminophenyl, 3-methylaminophenyl, 4-ethylaminophenyl, 3-propylaminophenyl, 4-butylaminophenyl, 3-dimethylaminophenyl, 4-diethylaminophenyl, 3-dipropylaminophenyl, 4-dibutylaminophenyl, 3-benzylphenyl, 4-benzylphenyl, 3-phenethylphenyl, 4-(1-naphthylmethyl)phenyl, 3-biphenylyl, 4-biphenylyl, 3-(4-methylphenyl)phenyl, 4-(4-methylphenyl)phenyl, 3-(4-ethylphenyl)phenyl, 3-(4-trifluoromethylphenyl)phenyl, 4-(4-trifluoromethylphenyl)phenyl, 4-(2-hydroxyphenyl)phenyl, 4-(3-hydroxyphenyl)phenyl, 4-(4-hydroxyphenyl)phenyl, 4-(4-hydroxy-3,5-dimethylphenyl)phenyl, 3-(4-methoxyphenyl)phenyl, 4-(2-methoxyphenyl)phenyl, 4-(3-methoxyphenyl)phenyl, 4-(4-methoxyphenyl)phenyl, 3-(2,4-dimethoxyphenyl)phenyl, 4-(2,4-dimethoxyphenyl)phenyl, 3-(2,5-dimethoxyphenyl)phenyl, 4-(2,5-dimethoxyphenyl)phenyl, 4-(3-hydroxymethylphenyl)phenyl, 4-(4-hydroxymethylphenyl)phenyl, 4-(3-fluorophenyl)phenyl, 4-(4-fluorophenyl)phenyl 4-(3-chlorophenyl)phenyl, 4-(4-chlorophenyl)phenyl, 4-(3-bromophenyl)phenyl 4-(4-bromophenyl)phenyl, 3-(3,4-methylenedioxyphenyl)phenyl, 4-(3,4-methylenedioxyphenyl)phenyl, 4-(2-formylphenyl)phenyl, 4-(3-formylphenyl)phenyl, 4-(4-formylphenyl)phenyl, 4-(3-carboxyphenyl)phenyl, 4-(4-carboxyphenyl)phenyl, 4-(3-N,N-dimethylaminomethylphenyl)phenyl, 4-(4-N,N-dimethylaminomethylphenyl)phenyl, 3-benzylphenyl, 4-benzylphenyl, 3-phenoxyphenyl, 4-phenoxyphenyl, 3-phenylthiophenyl, 4-phenylthiophenyl, 3-phenylsulfonylphenyl, 4-phenylsulfonylphenyl, 3-(phenylsulfonylamino)phenyl, 4-(phenylsulfonylamino)phenyl, 3-(N-methylphenylsulfonylamino)phenyl, 4-(N-methylphenylsulfonylamino)phenyl, 3-(imidazol-1-yl)phenyl, 4-(imidazol-1-yl)phenyl, 3-(1-methylimidazol-4-yl)phenyl, 4-(1-methylimidazol-4-yl)phenyl, 3-(2-furyl)phenyl, 4-(2-furyl)phenyl, 3-(2-thienyl)phenyl, 4-(2-thienyl)phenyl, 3-(3-thienyl)phenyl, 4-(3-thienyl)phenyl, 3-(2-pyridyl)phenyl, 4-(2-pyridyl)phenyl, 4-(2-trifluoromethylpyridin-5-yl)phenyl, 4-(2-methoxypyridin-5-yl)phenyl, 4-(2-nitropyridin-5-yl)phenyl, 4-(2-N,N-dimethylaminopyridin-5-yl)phenyl, 3-(3-pyridyl)phenyl, 4-(3-pyridyl)phenyl, 3-(4-pyridyl)phenyl, 4-(4-pyridyl)phenyl, 4-(imidazol-1-ylthio)phenyl, 4-(2-furylthio)phenyl, 4-(2-thienylthio)phenyl, 4-(2-pyridylthio)phenyl, 4-(4-pyridylthio)phenyl, 3-(2-pyridylsulfonyl)phenyl, 4-(2-pyridylsulfonyl)phenyl, 3-(3-pyridylsulfonyl)phenyl, 4-(3-pyridylsulfonyl)phenyl, 3-(2-pyridylsulfonylamino)phenyl, 3-(N-methyl-2-pyridylsulfonylamino)phenyl, 4-(2-pyridylsulfonylamino)phenyl, 4-(N-methyl-2-pyridylsulfonylamino)phenyl, 3-(3-pyridylsulfonylamino)phenyl, 3-(N-methyl-3-pyridylsulfonylamino)phenyl, 4-(3-pyridylsulIfonylamino)phenyl, 4-(N-methyl-3-pyridylsulfonylamino)phenyl, 3-(oxazol-2-yl)phenyl, 4-(oxazol-2-yl)phenyl, 3-(oxazol-4-yl)phenyl, 4-(oxazol4-yl)phenyl, 3-(oxazol-5-yl)phenyl, 4-(oxazol-5-yl)phenyl, 3-(thiazol-2-yl)phenyl, 4-(thiazol-2-yl)phenyl, 3-(thiazol-4-yl)phenyl, 4-(thiazol-4-yl)phenyl, 3-(thiazol-5-yl)phenyl, 4-(thiazol-5-yl)phenyl, 4-(piperidin-1-yl)phenyl, 1-methyl-2-pyrrolyl, 1-phenyl-2-pyrrolyl, 1-benzyl-2-pyrrolyl, 5-methyl-2-furyl, 5-phenyl-2-furyl, 5-methyl-2-thienyl, 5-phenyl-2-thienyl, 5-methyl-3-thienyl, 5-phenyl-3-thienyl, 1-methyl-3-pyrazolyl, 1-phenyl-3-pyrazolyl, 3-imidazolyl, 1-methyl-2-imidazolyl, 1-phenyl-2-imidazolyl, 1-methyl-4-imidazolyl, 1-phenyl-4-imidazolyl, 1-methyl-2-phenyl-4-imidazolyl, 1,5-dimethyl-2-phenyl-4-imidazolyl, 1,4-dimethyl-2-phenyl-5-imidazolyl, 4-oxazolyl, 5-oxazolyl, 2-methyl-4-oxazolyl, 2-phenyl-4-oxazolyl, 2-methyl-5-oxazolyl, 2-phenyl-5-oxazolyl, 4-methyl-2-phenyl-5-oxazolyl, 5-methyl-2-phenyl-4-oxazolyl, 4-thiazolyl, 5-thiazolyl, 2-methyl-4-thiazolyl, 2-phenyl-4-thiazolyl, 2-methyl-5-thiazolyl, 2-phenyl-5-thiazolyl, 4-methyl-2-phenyl-5-thiazolyl, 5-methyl-2-phenyl-4-thiazolyl, 1-methyl-3-pyrazolyl, 1-phenyl-3-pyrazolyl, 3-methyl-5-isoxazolyl, 3-phenyl-5-isoxazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 3-methyl-5-pyridyl, 3-ethyl-5-pyridyl, 3-phenyl-5-pyridyl, 2-methyl-5-pyridyl, 2-ethyl-5-pyridyl, 2-phenyl-5-pyridyl, 2-(4-methoxyphenyl)-5-pyridyl, 2-(4-fluorophenyl)-5-pyridyl, 2-hydroxy-5-pyridyl, 2-methoxy-5-pyridyl, 2-ethoxy-5-pyridyl, 2-isopropoxy-5-pyridyl, 2-(2,2,3,3-tetrafluoropropoxyphenyl)-5-pyridyl, 2-benzyloxy-5-pyridyl, 2-methylthio-5-pyridyl, 2-ethylthio-5-pyridyl, 2-isopropylthio-5-pyridyl, 2-methanesulfonyl-5-pyridyl, 2-ethanesulfonyl-5-pyridyl, 2-isopropanesulfonyl-5-pyridyl, 2-benzyl-5-pyridyl, 2-phenoxy-5-pyridyl, 2-phenylthio-5-pyridyl, 2-phenylsulfonyl-5-pyridyl, 2-phenylsulfonylamino-5-pyridyl, 2-(N-methyl-phenylsulfonylamino)-5-pyridyl, 3-methyl-6-pyridyl, 3-phenyl-6-pyridyl, 2-methyl-6-pyridyl, 2-phenyl-6-pyridyl, 2-methyl-4-pyrimidinyl, 2-phenyl-4-pyrimidinyl, 2-methoxy-4-pyrimidinyl, 2-ethoxy-4-pyrimidinyl, 2-isopropoxy-4-pyrimidinyl, 2-methylthio-4-pyrimidinyl, 2-ethylthio-4-pyrimidinyl, 2-isopropylthio-4-pyrimidinyl, 2-phenylthio-4-pyrimidinyl, 2-methanesulfonyl-4-pyrimidinyl, 2-ethanesulfonyl-4-pyrimidinyl, 2-isopropylsulfonyl-4-pyrimidinyl, 2-phenylsulfonyl4-pyrimidinyl, 2-methyl-5-pyrimidinyl, 2-phenyl-5-pyrimidinyl, 2-methoxy-5-pyrimidinyl, 2-ethoxy-5-pyrimidinyl, 2-isopropoxy-5-pyrimidinyl, 2-methylthio-5-pyrimidinyl, 2-ethylthio-5-pyrimidinyl, 2-isopropylthio-5-pyrimidinyl, 2-phenylthio-5-pyrimidinyl, 2-methanesulfonyl-5-pyrimidinyl, 2-ethanesulfonyl-5-pyrimidinyl, 2-isopropylsulfonyl-5-pyrimidinyl, 2-phenylsulfonyl-5-pyrimidinyl, 2-indolyl, 3-indolyl, 1-methyl-2-indolyl, 1-methyl-3-indolyl, 2-benzimidazolyl, 1-methyl-2-benzimidazolyl, 2-benzoxazolyl, 2-benzothiazolyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl or 8-isoquinolyl group;
preferably a phenyl, 1-naphthyl, 2-naphthyl, m-tolyl, p-tolyl, 3-ethylphenyl, 4-ethylphenyl, 3-isopropylphenyl, 4-isopropylphenyl, 4-trifluoromethylphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 4-hydroxy-3,5-dimethylphenyl, 3-acetoxyphenyl, 4-acetoxyphenyl, 5-acetoxy-2-hydroxy-3 ,4,6-trimethylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 3-isopropoxyphenyl, 4-isopropoxyphenyl, 3,4-methylenedioxyphenyl, benzyloxyphenyl, 3-methylthiophenyl, 4-methylthiophenyl, 3-ethylthiophenyl, 4-ethylthiophenyl, 3-methanesulfonylphenyl, 4-methanesulfonylphenyl, 3-ethanesulfonylphenyl, 4-ethanesulfonylphenyl, 3-fluorophenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-diethylaminophenyl, 3-benzylphenyl, 4-benzylphenyl, 3-biphenylyl, 4-biphenylyl, 3-(4-methylphenyl)phenyl, 4-(4-methylphenyl)phenyl, 3-(4-ethylphenyl)phenyl, 3-(4-trifluoromethylphenyl)phenyl, 4-(4-trifluoromethylphenyl)phenyl, 4-(2-hydroxyphenyl)phenyl, 4-(3-hydroxyphenyl)phenyl, 4-(4-hydroxyphenyl)phenyl, 4-(4-hydroxy-3,5-dimethylphenyl)phenyl, 3-(4-methoxyphenyl)phenyl, 4-(2-methoxyphenyl)phenyl, 4-(3-methoxyphenyl)phenyl, 4-(4-methoxyphenyl)phenyl, 3-(2,4-dimethoxyphenyl)phenyl, 4-(2,4-dimethoxyphenyl)phenyl, 3-(2,5-dimethoxyphenyl)phenyl, 4-(2,5-dimethoxyphenyl)phenyl, 4-(3-hydroxymethylphenyl)phenyl, 4-(4-hydroxymethylphenyl)phenyl, 4-(3-fluorophenyl)phenyl, 4-(4-fluorophenyl)phenyl, 4-(3-chlorophenyl)phenyl, 4-(4-chlorophenyl)phenyl, 3-(3,4-methylenedioxyphenyl)phenyl, 4-(3,4-methylenedioxyphenyl)phenyl, 2-formylphenyl, 3-formylphenyl, 4-formylphenyl, 3-carboxyphenyl, 4-carboxyl, 3-N,N-dimethylaminomethylphenyl, 4-N,N-dimethylaminomethylphenyl, 3-phenoxyphenyl, 4-phenoxyphenyl, 3-phenylthiophenyl, 4-phenylthiophenyl, 3-phenylsulfonylphenyl, 4-phenylsulfonylphenyl, 3-(phenylsulfonylamino)phenyl, 4-(phenylsulfonylamino)phenyl, 3-(N-methylphenylsulfonylamino)phenyl, 4-(N-methylphenylsulfonylamino)phenyl, 3-(2-pyridyl)phenyl, 4-(2-pyridyl)phenyl, 4-(2-trifluoromethylpyridin-5-yl)phenyl, 4-(2-methoxypyridin-5-yl)phenyl, 4-(2-nitropyridin-5-yl)phenyl, 4-(2-N,N-dimethylaminopyridin-5-yl)phenyl, 3-(3-pyridyl)phenyl, 4-(3-pyridyl)phenyl, 3-(4-pyridyl)phenyl, 4-(4-pyridyl)phenyl, 4-(2-pyridyloxy)phenyl, 4-(4-pyridyloxy)phenyl, 4-(2-pyridylthio)phenyl, 4-(4-pyridylthio)phenyl, 3-(2-pyridylsulfonyl)phenyl, 4-(2-pyridylsulfonyl)phenyl, 3-(3-pyridylsulfonyl)phenyl, 4-(3-pyridylsulfonyl)phenyl, 3-(2-pyridylsulfonylamino)phenyl, 3-(N-methyl-2-pyridylsulfonylamino)phenyl, 4-(2-pyridylsulfonylamino)phenyl, 4-(N-methyl-2-pyridylsulfonylamino)phenyl 3-(3-pyridylsulfonylamino)phenyl, 3-(N-methyl-3-pyridylsulfonylamino)phenyl, 4-(3-pyridylsulfonylamino)phenyl, 4-(N-methyl-3-pyridylsulfonylamino)phenyl 4-(1-piperidinyl)phenyl, 3-imidazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 3-methyl-5-pyridyl, 3-ethyl-5-pyridyl, 3-phenyl-5-pyridyl, 2-methyl-5-pyridyl, 2-ethyl-5-pyridyl 2-phenyl-5-pyridyl, 2-hydroxy-5-pyridyl, 2-methoxy-5-pyridyl, 2-ethoxy-5-pyridyl, 2-isopropoxy-5-pyridyl, 2-(2,2,3,3-tetrafluoropropoxy)-5-pyridyl, 2-benzyloxy-5-pyridyl, 2-methylthio-5-pyridyl, 2-ethylthio-5-pyridyl, 2-isopropylthio-5-pyridyl, 2-methanesulfonyl-5-pyridyl, 2-ethanesulfonyl-5-pyridyl, 2-isopropanesulfonyl-5-pyridyl, 2-benzyl-5-pyridyl, 2-phenoxy-5-pyridyl, 2-phenylthio-5-pyridyl, 2-phenylsulfonyl-5-pyridyl, 2-phenylsulfonylamino-5-pyridyl, 2-(N-methyl-phenylsulfonylamino)-5-pyridyl, 2-(4-methoxyphenyl)-5-pyridyl, 2-(4-fluorophenyl)-5-pyridyl, 3-methyl-6-pyridyl, 3-phenyl-6-pyridyl, 2-methyl-6-pyridyl, 2-phenyl-6-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl or 8-isoquinolyl group;
more preferably a phenyl, m-tolyl, p-tolyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 4-hydroxy-3,5-dimethylphenyl, 3-acetoxyphenyl, 4-acetoxyphenyl, 5-acetoxy-2-hydroxy-3,4,6-trimethylphenyl, 3-chlorophenyl, 4-chlorophenyl, 3-benzylphenyl, 4-benzylphenyl, 3-biphenylyl, 4-biphenylyl, 4-(4-trifluoromethylphenyl)phenyl, 4-(2-hydroxyphenyl)phenyl, 4-(3-hydroxyphenyl)phenyl, 4-(4-hydroxyphenyl)phenyl, 4-(2-methoxyphenyl)phenyl, 4-(3-methoxyphenyl)phenyl, 4-(4-methoxyphenyl)phenyl, 4-(4-hydroxy-3,5-dimethylphenyl)phenyl, 4-(4-fluorophenyl)phenyl, 4-(4-chlorophenyl)phenyl, 4-(2-formylphenyl)phenyl, 4-(3-formylphenyl)phenyl, 4-(4-formylphenyl)phenyl, 4-(3-carboxyphenyl)phenyl, 4-(4-carboxyphenyl)phenyl, 4-(3-hydroxymethylphenyl)phenyl, 4-(4-hydroxymethylphenyl)phenyl, 4-(3-N,N-dimethylaminomethylphenyl)phenyl, 4-(4-N,N-dimethylaminomethylphenyl)phenyl, 3-phenoxyphenyl, 4-phenoxyphenyl, 3-phenylthiophenyl, 4-phenylthiophenyl, 3-phenylsulfonylphenyl, 4-phenylsulfonylphenyl, 3-(phenylsulfonylamino)phenyl, 4-(phenylsulfonylamino)phenyl, 3-(N-methylphenylsulfonylamino)phenyl, 4-(N-methylphenylsulfonylamino)phenyl, 3-(2-pyridyl)phenyl, 4-(2-pyridyl)phenyl, 4-(3-trifluoromethylpyridin-6-yl)phenyl, 4-(3-methoxypyridin-6-yl)phenyl, 4-(3-nitropyridin-6-yl)phenyl, 4-(3-N,N-dimethylaminopyridin-6-yl)phenyl, 3-(3-pyridyl)phenyl, 4-(3-pyridyl)phenyl, 3-(4-pyridyl)phenyl, 4-(4-pyridyl)phenyl, 4-(2-pyridyloxy)phenyl, 4-(4-pyridyloxy)phenyl, 4-(2-pyridylthio)phenyl, 4-(4-pyridylthio)phenyl, 3-(2-pyridylsulfonyl)phenyl, 4-(2-pyridylsulfonyl)phenyl, 3-(3-pyridylsulfonyl)phenyl, 4-(3-pyridylsulfonyl)phenyl, 3-(2-pyridylsulfonylamino)phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-methoxy-5-pyridyl, 2-ethoxy-5-pyridyl, 2-isopropoxy-5-pyridyl, 2-(2,2,3,3-tetrafluoropropoxy)-5-pyridyl, 2-benzyloxy-5-pyridyl, 2-methylthio-5-pyridyl, 2-ethylthio-5-pyridyl, 2-methanesulfonyl-5-pyridyl, 2-ethanesulfonyl-5-pyridyl, 2-benzyl-5-pyridyl, 2-phenyl-5-pyridyl, 2-(4-methoxyphenyl)-5-pyridyl, 2-(4-fluorophenyl)-5-pyridyl, 3-phenyl-5-pyridyl, 2-phenyl-6-pyridyl, 3-phenyl-6-pyridyl, 2-phenoxy-5-pyridyl, 2-phenylthio-5-pyridyl, 2-phenylsulfonyl-5-pyridyl, 2-phenylsulfonylamino-5-pyridyl, 2-(N-methylphenylsulfonylamino)-5-pyridyl, 2-methyl-5-pyridyl, 3-quinolyl, 3-methyl-S-pyridyl, 3-quinolyl or 3-indolyl group;
most preferably a phenyl, p-tolyl, 4-fluorophenyl, 4-benzylphenyl, 4-biphenylyl, 4-(4-trifluoromethylphenyl)phenyl, 4-(2-hydroxyphenyl)phenyl, 4-(3-hydroxyphenyl)phenyl, 4-(4-hydroxyphenyl)phenyl, 4-(2-methoxyphenyl)phenyl, 4-(3-methoxyphenyl)phenyl, 4-(4-methoxyphenyl)phenyl, 4-(4-hydroxy-3,5-dimethylphenyl)phenyl, 4-(4-fluorophenyl)phenyl, 4-(4-chlorophenyl)phenyl, 4-(2-formylphenyl)phenyl, 4-(3-formylphenyl)phenyl, 4-(4-formylphenyl)phenyl, 4-(3-carboxyphenyl)phenyl, 4-(4-carboxyphenyl)phenyl, 4-(3-hydroxymethylphenyl)phenyl, 4-(4-hydroxymethylphenyl)phenyl, 4-(3-N,N-dimethylaminomethylphenyl)phenyl, 4-(4-N,N-dimethylaminomethylphenyl)phenyl, 4-phenoxyphenyl, 4-phenylthiophenyl, 4-phenylsulfonylphenyl, 4-(phenylsulfonylamino)phenyl, 4-(2-pyridyl)phenyl, 4-(3-trifluoromethylpyridin-6-yl)phenyl, 4-(3-methoxypyridin-6-yl)phenyl, 4-(3-nitropyridin-6-yl)phenyl, 4-(3-N,N-dimethylaminopyridin-6-yl)phenyl, 4-(3-pyridyl)phenyl, 4-(4-pyridyl)phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-methoxy-5-pyridyl, 2-ethoxy-5-pyridyl, 2-isopropoxy-5-pyridyl, 2-(2,2,3,3-tetrafluoropropoxy)-5-pyridyl, 2-benzyloxy-5-pyridyl, 2-methylthio-5-pyridyl, 2-ethylthio-5-pyridyl, 2-methanesulfonyl-5-pyridyl, 2-ethanesulfonyl-5-pyridyl, 2-benzyl-5-pyridyl, 2-phenyl-5-pyridyl, 3-phenyl-5-pyridyl, 3-phenyl-6-pyridyl, 2-(4-methoxyphenyl)-5-pyridyl, 2-(4-fluorophenyl)-5-pyridyl, 2-phenyl-6-pyridyl, 2-phenoxy-5-pyridyl, 2-phenylthio-5-pyridyl, 2-phenylsulfonyl-5-pyridyl, 2-phenylsulfonylamino-5-pyridyl, 2-(N-methylphenylsulfonylamino)-5-pyridyl, 2-methyl-5-pyridyl or 3-methyl-5-pyridyl group.
In the case where Y represents a group of the formula:  greater than Nxe2x80x94R5 (wherein R5 represents a hydrogen atom, a straight or branched chain alkyl group having from 1 to 6 carbon atoms (the alkyl group has the same meaning as described above in the definition of R3) or a straight or branched chain aliphatic acyl group having from 1 to 8 carbon atoms (the aliphatic acyl group includes, for example, an alkanoyl group having from 1 to 8 carbon atoms and an alkenoyl group having from 3 to 8 carbon atoms) or an aromatic acyl group having from 7 to 11 carbon atoms), the group of the formula:  greater than Nxe2x80x94R5 includes, for example, an imino, methylimino, ethylimino, propylimino, isopropylimino, butylimino, isobutylimino, s-butylimino, t-butylimino, pentylimino, 1-methylbutylimino, 2-methylbutylimino, 3-methylbutylimino, 1,1-dimethylpropylimino, 1,2-dimethylpropylimino, 2,2-dimethylpropylimino, 1-ethylpropylimino, hexylimino, 1-methylpentylimino, 2-methylpentylimino, 3-methylpentylimino, 4-methylpentylimino, 1,1-dimethylbutylimino, 1,2-dimethylbutylimino, 1,3-dimethylbutylimino, 2,2-dimethylbutylimino, 2,3-dimethylbutylimino, 3,3-dimethylbutylimino, 1-ethylbutylimino, 1,1,2-trimethylpropylimino, 1,2,2-trimethylpropylimino, acetylimino, propionylimino, butyrylimino, pentanoylimino, hexanoylimino, heptanoylimino, octanoylimino, benzoylimino or p-toluoylimino group;
preferably an imino group, a straight or branched chain alkylimino group having from 1 to 4 carbon atoms or an acetylimino group;
most preferably an imino, methylimino, ethylimino or acetylimino group.
The amidocarboxylic acid derivatives of the formula (I) of the present invention can be converted to an acid addition salt according to a conventional method in the case where it has a basic group. Such salts include salts of hydrohalogenic acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid and hydroiodic acid; inorganic acid salts such as a nitrate, perchlorate, sulfate and phosphate; salts of lower alkanesulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid and ethanesulfonic acid; salts of arylsulfonic acid such as benzenesulfonic acid and p-toluenesulfonic acid; salts of amino acids such as glutamic acid and aspartic acid; and salts of carboxylic acids such as acetic acid, fumaric acid, tartaric acid, oxalic acid, maleic acid, malic acid, succinic acid, benzoic acid, mandelic acid, ascorbic acid, lactic acid, gluconic acid and citric acid; preferably salts of hydrohalogenic acids.
Further, the amidocarboxylic acid derivatives of the formula (I) can be converted to a metal salt according to a conventional method since it has a carboxyl group. Such salts include alkali metal salts such as lithium, sodium and potassium; alkaline earth metal salts such as calcium, barium and magnesium; and aluminum salts, preferably alkali metal salts.
The amidocarboxylic acid derivatives of the formula (I) of the present invention can be converted to a pharmacologically acceptable ester according to a conventional method. The pharmacologically acceptable ester of the amidocarboxylic acid derivative of the formula (I) is not particularly limited so long as it can be medically used and pharmacologically accepted in comparison with the amidocarboxylic acid of the formula (I).
The esters of the amidocarboxylic acid derivatives of the formula (I) of the present invention includes a straight or branched chain alkyl group having from 1 to 6 carbon atoms; an aralkyl group having from 7 to 19 carbon atoms; a straight or branched chain alkyl group having from 1 to 5 carbon atoms which is substituted by a straight or branched chain alkanoyloxy group having from 1 to 6 carbon atoms; a straight or branched chain alkyl group having from 1 to 5 carbon atoms which is substituted by a straight or branched chain alkyloxycarbonyloxy group having from 1 to 6 carbon atoms; a straight or branched chain alkyl group having from 1 to 5 carbon atoms which is substituted by a cycloalkylcarbonyloxy group having from 5 to 7 carbon atoms; a straight or branched chain alkyl group having from 1 to 5 carbon atoms which is substituted by a cycloalkyloxycarbonyloxy group having from 5 to 7 carbon atoms; a straight or branched chain alkyl group having from 1 to 5 carbon atoms which is substituted by an arylcarbonyloxy group having from 6 to 10 carbon atoms; a straight or branched chain alkyl group having from 1 to 5 carbon atoms which is substituted by an aryloxycarbonyloxy group having from 6 to 10 carbon atoms; or a 2-oxo-1,3-dioxolen-4-ylmethyl group having a straight or branched chain alkyl group having from 1 to 6 carbon atoms as a substituent at the 5-position.
The straight or branched chain alkyl group having from 1 to 4 carbon atoms and the straight or branched chain alkyl group having from 1 to 6 carbon atoms include a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl or 1,2,2-trimethylpropyl group; preferably a straight or branched chain alkyl group having from 1 to 4 carbon atoms; more preferably a methyl, ethyl, propyl, isopropyl, butyl or isobutyl group; most preferably a methyl or ethyl group.
The aralkyl group having from 7 to 19 carbon atoms includes a benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, 1-naphthylmethyl, 2-naphthylmethyl or diphenylmethyl group; preferably a benzyl group.
The cycloalkyl group having from 5 to 7 carbon atoms includes a cyclopentyl, cyclohexyl or cycloheptyl group; preferably a cyclohexyl group.
The aryl group having from 6 to 10 carbon atoms includes a phenyl or naphthyl group; preferably the phenyl group.
The specific example of the preferable ester residue a includes a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, benzyl, acetoxymethyl, 1-(acetoxy)ethyl, propionyloxymethyl, 1-(propionyloxy)ethyl, butyryloxymethyl, 1-(butyryloxy)ethyl, isobutyryloxymethyl, 1-(isobutyryloxy)ethyl, valeryloxymethyl, 1-(valeryloxy)ethyl, isovaleryloxymethyl, 1-(isovaleryloxy)ethyl, pivaloyloxymethyl, 1-(pivaloyloxy)ethyl, methoxycarbonyloxymethyl, 1-(methoxycarbonyloxy)ethyl, ethoxycarbonyloxymethyl, 1-(ethoxycarbonyloxy)ethyl, propoxycarbonyloxymethyl, 1-(propoxycarbonyloxy)ethyl, isopropoxycarbonyloxymethyl, 1-(isopropoxycarbonyloxy)ethyl, butoxycarbonyloxymethyl, 1-(butoxycarbonyloxy)ethyl, isobutoxycarbonyloxymethyl, 1-(isobutoxycarbonyloxy)ethyl, t-butoxycarbonyloxymethyl, 1-(t-butoxycarbonyloxy)ethyl, cyclopentanecarbonyloxymethyl, 1-(cyclopentanecarbonyloxy)ethyl, cyclohexanecarbonyloxymethyl, 1-(cyclohexanecarbonyloxy)ethyl, cyclopentyloxycarbonyloxymethyl, 1-(cyclopentyloxycarbonyloxy)ethyl, cyclohexyloxycarbonyloxymethyl, 1-(cyclohexyloxycarbonyloxy)ethyl, benzoyloxymethyl, 1-(benzoyloxy)ethyl, phenoxycarbonyloxymethyl, 1-(phenoxycarbonyloxy)ethyl or 5-methyl-2-oxo-1,3-dioxolen4-ylmethyl group.
Incidentally, the amidocarboxylic acid derivatives of the formula (I), the pharmacologically acceptable salts thereof or the pharmacologically acceptable esters thereof have various isomers. For example, an optical isomer derived from an asymmetric carbon at the xcex1-position of the carboxylic acid exists. In the formula (I), all of the stereoisomers based on these asymmetric carbon atoms and the equivalent and non-equivalent mixtures of these isomers are shown by a single formula. Therefore, the present invention includes all of these isomers and a mixture of these isomers.
Moreover, in the present invention, in the case where the amidocarboxylic acid derivative of the formula (I), the pharmacologically acceptable salts thereof and the pharmacologically acceptable esters thereof form solvates (for example, hydrates), the present invention includes all of these solvates.
Further, the present invention includes all compounds which are metabolized in living bodies and are converted to the amidocarboxylic acid derivatives of the formula (I) or a salt thereof, for example, so-called prodrugs such as amide derivatives.
The amidocarboxylic acid derivatives of the formula (I) preferably include:
(1) amidocarboxylic acid derivatives in which R1 is a hydrogen atom, a straight or branched chain alkyl group having from 1 to 4 carbon atoms or an aralkyl group having from 7 to 9 carbon atoms, pharmacologically acceptable salts thereof or pharmacologically acceptable esters thereof;
(2) amidocarboxylic acid derivatives in which R1 is a hydrogen atom or a straight or branched chain alkyl group having from 1 to 4 carbon atoms, pharmacologically acceptable salts thereof or pharmacologically acceptable esters thereof;
(3) amidocarboxylic acid derivatives in which R1 is a hydrogen atom or an alkyl group having one or two carbon atoms, pharmacologically acceptable salts thereof or pharmacologically acceptable esters thereof;
(4) amidocarboxylic acid derivatives in which R1 is a hydrogen atom, pharmacologically acceptable salts thereof or pharmacologically acceptable esters thereof;
(5) amidocarboxylic acid derivatives in which R2 is a straight or branched chain alkylene group having from 2 to 5 carbon atoms, pharmacologically acceptable salts thereof or pharmacologically acceptable esters thereof.
(6) amidocarboxylic acid derivatives in which R2 is a straight or branched chain alkylene group having from 2 to 4 carbon atoms, pharmacologically acceptable salts thereof or pharmacologically acceptable esters thereof;
(7) amidocarboxylic acid derivatives in which R2 is an ethylene group a trimethylene group or a methylethylene group, pharmacologically acceptable salts thereof or pharmacologically acceptable esters thereof;
(8) amidocarboxylic acid derivatives in which R2 is an ethylene group, pharmacologically acceptable salts thereof or pharmacologically acceptable esters thereof;
(9) amidocarboxylic acid derivatives in which R3 is a hydrogen atom, a straight or branched chain alkyl group having from 1 to 4 carbon atoms, an alkoxy group having one or two carbon atoms, an alkylthio group having one or two carbon atoms, a halogen atom, a nitro group, a hydroxyl group or a straight or branched chain aliphatic acyl group having from 1 to 5 carbon atoms, pharmacologically acceptable salts thereof or pharmacologically acceptable esters thereof;
(10) amidocarboxylic acid derivatives in which R3 is a hydrogen atom, a halogen atom or a nitro group, pharmacologically acceptable salts thereof or pharmacologically acceptable esters thereof;
(11) amidocarboxylic acid derivatives in which R3 is a hydrogen atom, pharmacologically acceptable salts thereof or pharmacologically acceptable esters thereof;
(12) amidocarboxylic acid derivatives in which R4 is a hydrogen atom or a straight or branched chain alkyl group having from 1 to 4 carbon atoms, pharmacologically acceptable salts thereof or pharmacologically acceptable esters thereof;
(13) amidocarboxylic acid derivatives in which R4 is a hydrogen atom or an alkyl group having one or two carbon atoms, pharmacologically acceptable salts thereof or pharmacologically acceptable esters thereof;
(14) amidocarboxylic acid derivatives in which R4 is a hydrogen atom or a methyl group, pharmacologically acceptable salts thereof or pharmacologically acceptable esters thereof;
(15) amidocarboxylic acid derivatives in which R4 is a hydrogen atom, pharmacologically acceptable salts thereof or pharmacologically acceptable esters thereof;
(16) amidocarboxylic acid derivatives in which R4 is a methyl group, pharmacologically acceptable salts thereof or pharmacologically acceptable esters thereof;
(17) amidocarboxylic acid derivatives in which Z is a straight or branched chain alkylene group having from 1 to 4 carbon atoms, pharmacologically acceptable salts thereof or pharmacologically acceptable esters thereof;
(18) amidocarboxylic acid derivatives in which Z is an alkylene group having one or two carbon atoms, pharmacologically acceptable salts thereof or pharmacologically acceptable esters thereof;
(19) amidocarboxylic acid derivatives in which Z is a methylene group, pharmacologically acceptable salts thereof or pharmacologically acceptable esters thereof;
(20) amidocarboxylic acid derivatives in which W represents (i) a straight or branched chain alkyl group having from 1 to 6 carbon atoms, (ii) a hydroxyl group, (iii) a straight or branched chain alkoxy group having from 1 to 4 carbon atoms, (iv) a straight or branched chain alkylthio group having from 1 to 4 carbon atoms, (v) an aryl group having from 6 to 10 carbon atoms which may have from 1 to 3 substituents xcex11 described later, (vi) an aryloxy group having from 6 to 10 carbon atoms which may have from 1 to 3 substituents al described later on the aryl moiety, (vii) an arylthio group having from 6 to 10 carbon atoms which may have from 1 to 3 substituents xcex11 described later on the aryl moiety, (viii) an aralkyl group having from 7 to 12 carbon atoms which may have from-1 to 3 substituents xcex11 described later on the aryl moiety, (ix) an aralkyloxy group having from 7 to 12 carbon atoms which may have from 1 to 3 substituents xcex11 described later on the aryl moiety, (x) an aralkylthio group having from 7 to 12 carbon atoms which may have from 1 to 3 substituents xcex11 described later on the aryl moiety, (xi) an aryloxyalkyl group in which the aryl moiety is an aryl group having from 6 to 10 carbon atoms which may have from 1 to 3 substituents xcex11 described later and the alkyl moiety is a straight or branched chain alkyl group having from 1 to 4 carbon atoms, (xii) a mono- or dicyclic, 5- to 10-membered hetero aryl group containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, nitrogen atom and sulfur atom, (xiii) a mono- or dicyclic, 5- to 10-membered hetero aryloxy group containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, nitrogen atom and sulfur atom, (xiv) a mono- or dicyclic, 5- to 10-membered hetero arylthio group containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, nitrogen atom and sulfur atom or (xv) a mono- or dicyclic, 5- to 10-membered saturated heterocyclic group containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, nitrogen atom and sulfur atom,
here, the substituent xcex11 represents a group selected from the group consisting of (i) straight or branched chain alkyl groups having from 1 to 6 carbon atoms, (ii) straight or branched chain halogenated alkyl groups having from 1 to 4 carbon atoms, (iii) hydroxyl groups, (iv) straight or branched chain aliphatic acyloxy groups having from 1 to 5 carbon atoms, (v) straight or branched chain aliphatic acyl groups having from 1 to 5 carbon atoms, (vi) straight or branched chain alkoxy groups having from 1 to 4 carbon atoms, (vii) straight or branched chain halogenated alkoxy groups having from 1 to 4 carbon atoms, (viii) straight or branched chain alkylenedioxy groups having from 1 to 4 carbon atoms, (ix) aralkyloxy groups having from 7 to 12 carbon atoms which may have from 1 to 3 substituents xcex21 described later, (x) straight or branched chain alkylthio groups having from 1 to 4 carbon atoms, (xi) straight or branched chain alkylsulfonyl groups having from 1 to 4 carbon atoms, (xii) halogen atoms, (xiii) nitro groups, (xiv) cyano groups, (xv) amino groups, (xvi) straight or branched chain monoalkylamino groups in which the alkyl moiety has from 1 to 4 carbon atoms, (xvii) straight or branched chain alkoxycarbonylamino groups in which the alkoxy moiety has from 1 to 4 carbon atoms, (xviii) aralkyloxycarbonylamino groups in which the aralkyl moiety has from 7 to 12 carbon atoms, (xix) straight or branched chain dialkylamino groups in which each alkyl group may be the same or different and each has from 1 to 4 carbon atoms, (xx) aralkyl groups having from 7 to 12 carbon atoms which may have from 1 to 3 substituents xcex21 described later on the aryl moiety, (xxi) aryl groups having from 6 to 10 carbon atoms which may have from 1 to 3 substituents xcex21, which may be the same or different, described later, (xxii) aryloxy groups having from 6 to 10 carbon atoms which may have from 1 to 3 substituents xcex21 described later on the aryl moiety, (xxiii) arylthio groups having from 6 to 10 carbon atoms which may have from 1 to 3 substituents xcex21 described later on the aryl moiety, (xxiv) arylsulfonyl groups having from 6 to 10 carbon atoms which may have from 1 to 3 substituents xcex21 described later on the aryl moiety, (xxv) arylsulfonylamino groups having from 6 to 10 carbon atoms which may have from 1 to 3 substituents xcex21 described later on the aryl moiety (the nitrogen atom of the amino moiety may be substituted with a straight or branched chain alkyl group having from 1 to 6 carbon atoms), (xxvi) mono- or dicyclic, 5- to 10-membered hetero aryl groups containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, nitrogen atom and sulfur atom which may have from 1 to 3 substituents xcex21 described later, (xxvii) mono- or dicyclic, 5- to 10-membered hetero aryloxy groups containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, nitrogen atom and sulfur atom which may have from 1 to 3 substituents xcex21 described later, (xxviii) mono- or dicyclic, 5- to 10-membered hetero arylthio groups containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, nitrogen atom and sulfur atom which may have from 1 to 3 substituents xcex21 described later, (xxix) mono- or dicyclic, 5- to 10-membered hetero arylsulfonyl groups containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, nitrogen atom and sulfur atom which may have from 1 to 3 substituents xcex21 described later, (xxx) mono- or dicyclic, 5- to 10-membered hetero arylsulfonylamino groups containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, nitrogen atom and sulfur atom which may have from 1 to 3 substituents xcex21 described later on the hetero aryl moiety (the nitrogen atom of the amino moiety may be substituted with a straight or branched chain alkyl having from 1 to 6 carbon atoms) and (xxxi) mono- or dicyclic, 5- to 10-membered saturated heterocyclic groups containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, nitrogen atom and sulfur atom,
here, the substituent xcex21 represents a group selected from the group consisting of (i) straight or branched chain alkyl groups having from 1 to 6 carbon atoms, (ii) straight or branched chain halogenated alkyl groups having from 1 to 4 carbon atoms, (iii) hydroxyl groups, (iv) straight or branched chain alkoxy groups having from 1 to 4 carbon atoms, (v) straight or branched chain halogenated alkoxy groups having from 1 to 4 carbon atoms, (vi) straight or branched chain alkylenedioxy groups having from 1 to 4 carbon atoms, (vii) straight or branched chain hydroxyalkyl groups having from 1 to 4 carbon atoms, (viii) halogen atoms, (ix) nitro groups, (x) formyl groups, (xi) cyano groups, (xii) carboxyl groups, (xiii) amino groups, (xiv) straight or branched chain monoalkylamino groups in which the alkyl moiety has from 1 to 4 carbon atoms, (xv) straight or branched chain dialkylamino groups in which each alkyl moiety may be the same or different and each has from 1 to 4 carbon atoms, (xvi) straight or branched chain aminoalkyl groups having from 1 to 4 carbon atoms, (xvii) monoalkylaminoalkyl groups in which the monoalkylamino moiety has one straight or branched chain alkyl group having from 1 to 4 carbon atoms and the alkyl moiety is a straight or branched chain alkyl group having from 1 to 4 carbon atoms, (xviii) dialkylaminoalkyl groups in which the dialkylamino moiety has two straight or branched chain alkyl groups having from 1 to 4 carbon atoms which may be the same or different and the alkyl moiety is a straight or branched chain alkyl group having from 1 to 4 carbon atoms, (xix) straight or branched chain alkoxycarbonylamino groups in which the alkoxy moiety has from 1 to 4 carbon atoms or (xx) aralkyloxycarbonylamino groups in which the aryl moiety has from 6 to 10 carbon atoms and the alkyl moiety has from 1 to 4 carbon atoms, pharmacologically acceptable salts thereof and pharmacologically acceptable esters thereof;
(21) amidocarboxylic acid derivatives in which W represents (i) a straight or branched chain alkyl group having from 1 to 6 carbon atoms, (ii) a hydroxyl group, (iii) a straight or branched chain alkoxy group having from 1 to 4 carbon atoms, (iv) a straight or branched chain alkylthio group having from 1 to 4 carbon atoms, (v) an aryl group having from 6 to 10 carbon atoms which may have from 1 to 3 substituents xcex12 described later, (vi) an aryloxy group having from 6 to 10 carbon atoms which may have from 1 to 3 substituents xcex12 described later on the aryl moiety, (vii) an arylthio group having from 6 to 10 carbon atoms which may have from 1 to 3 substituents xcex12 described later on the aryl moiety, (viii) an aralkyl group having from 7 to 12 carbon atoms which may have from 1 to 3 substituents xcex12 described later on the aryl moiety, (ix) an aralkyloxy group having from 7 to 12 carbon atoms which may have from 1 to 3 substituents xcex12 described later on the aryl moiety, (x) an aralkylthio group having from 7 to 12 carbon atoms which may have from 1 to 3 substituents xcex12 described later on the aryl moiety, (xi) an aryloxyalkyl group in which the aryl moiety is an aryl group having from 6 to 10 carbon atoms which may have from 1 to 3 substituents xcex12 described later and the alkyl moiety is a straight or branched chain alkyl group having from 1 to 4 carbon atoms, (xii) a mono- or dicyclic, 5- to 10-membered hetero aryloxy group containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, nitrogen atom and sulfur atom or (xiii) a mono- or dicyclic, 5- to 10-membered hetero arylthio group containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, nitrogen atom and sulfur atom,
here, the substituent xcex12 represents a group selected from the group consisting of (i) straight or branched chain alkyl groups having from 1 to 6 carbon atoms, (ii) straight or branched chain halogenated alkyl groups having from 1 to 4 carbon atoms, (iii) hydroxyl groups, (iv) straight or branched chain aliphatic acyloxy groups having from 1 to 5 carbon atoms, (v) straight or branched chain alkoxy groups having from 1 to 4 carbon atoms, (vi) straight or branched chain halogenated alkoxy groups having from 1 to 4 carbon atoms, (vii) straight or branched chain alkylthio groups having from 1 to 4 carbon atoms, (viii) straight or branched chain alkylsulfonyl groups having from 1 to 4 carbon atoms, (ix) halogen atoms, (x) nitro groups, (xi) cyano groups, (xii) straight or branched chain dialkylamino groups in which each alkyl group may be the same or different and each has from 1 to 4 carbon atoms, (xiii) aryl groups having from 6 to 10 carbon atoms which may be the same or different and have from 1 to 3 substituents xcex22 described later, (xiv) aryloxy groups having from 6 to 10 carbon atoms which may have from 1 to 3 substituents xcex22 described later on the aryl moiety, (xv) arylthio groups having from 6 to 10 carbon atoms which may have from 1 to 3 substituents xcex22 described later on the aryl moiety, (xvi) mono- or dicyclic, 5- to 10-membered hetero aryl groups containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, nitrogen atom and sulfur atom which may have from 1 to 3 substituents xcex22 described later, (xvii) mono- or dicyclic, 5- to 10-membered hetero aryloxy groups containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, nitrogen atom and sulfur atom which may have from 1 to 3 substituents xcex22 described later, (xviii) mono- or dicyclic, 5- to 10-membered hetero arylthio groups containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, nitrogen atom and sulfur atom which may have from 1 to 3 substituents xcex22 described later and (xix) mono- or dicyclic, 5- to 10-membered saturated heterocyclic groups containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, nitrogen atom and sulfur atom,
here, the substituent xcex22 represents a group selected from the group consisting of (i) straight or branched chain alkyl groups having from 1 to 6 carbon atoms, (ii) straight or branched chain halogenated alkyl groups having from 1 to 4 carbon atoms, (iii) straight or branched chain alkoxy groups having from 1 to 4 carbon atoms, (iv) straight or branched chain hydroxyalkyl groups having from 1 to 4 carbon atoms, (v) halogen atoms, (vi) nitro groups, (vii) formyl groups, (viii) carboxyl groups, (ix) straight or branched chain dialkylamino groups in which each alkyl group may be the same or different and each has from 1 to 4 carbon atoms or (x) dialkylaminoalkyl groups in which the dialkylamino moiety has two straight or branched chain alkyls groups having from 1 to 4 carbon atoms which may be the same or different and the alkyl moiety is a straight or branched chain alkyl group having from 1 to 4 carbon atoms, pharmacologically acceptable salts thereof or pharmacologically acceptable esters thereof;
(22) amidocarboxylic acid derivatives in which W represents (i) a straight or branched chain alkyl group having from 1 to 6 carbon atoms, (ii) a straight or branched chain alkoxy group having from 1 to 4 carbon atoms, (iii) an aryloxy group having from 6 to 10 carbon atoms which may have from 1 to 3 substituents xcex13 described later on the aryl moiety, (iv) an arylthio group having from 6 to 10 carbon atoms which may have from 1 to 3 substituents xcex13 described later on the aryl moiety, (v) an aralkyl group having from 7 to 12 carbon atoms which may have from 1 to 3 substituents xcex13 described later on the aryl moiety, (vi) an aralkyloxy group having from 7 to 12 carbon atoms which may have from 1 to 3 substituents xcex13 described later on the aryl moiety, (vii) an aryloxyalkyl group in which the aryl moiety is an aryl group having from 6 to 10 carbon atoms which may have from 1 to 3 substituents xcex13 described later and the alkyl moiety is a straight or branched chain alkyl group having from 1 to 4 carbon atoms, (viii) a mono- or dicyclic, 5- to 10-membered hetero aryloxy group containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, nitrogen atom and sulfur atom or (ix) a mono- or dicyclic, 5- to 10-membered hetero arylthio group containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, nitrogen atom and sulfur atom,
here, the substituent xcex13 represents a group selected from the group consisting of (i) straight or branched chain alkyl groups having from 1 to 6 carbon atoms, (ii) straight or branched chain halogenated alkyl groups having from 1 to 4 carbon atoms, (iii) straight or branched chain alkoxy groups having from 1 to 4 carbon atoms, (iv) straight or branched chain halogenated alkoxy groups having from 1 to 4 carbon atoms, (v) straight or branched chain alkylthio groups having from 1 to 4 carbon atoms, (vi) straight or branched chain alkylsulfonyl groups having from 1 to 4 carbon atoms, (vii) halogen atoms, (viii) cyano groups and (ix) pyridyl groups, pharmacologically acceptable salts thereof or pharmacologically acceptable esters thereof,
(23) amidocarboxylic acid derivatives in which W represents (i) a straight or branched chain alkyl group having from 1 to 6 carbon atoms, (ii) a straight or branched chain alkoxy group having from 1 to 4 carbon atoms, (iii) a phenoxy group which may have from 1 to 3 substituents xcex13 described later on the phenyl moiety, (iv) a phenylthio group having from 6 to 10 carbon atoms which may have from 1 to 3 substituents xcex14 described later on the phenyl moiety, (v) an aralkyl group having from 7 to 10 carbon atoms, (vi) an aralkyloxy group having from 7 to 10 carbon atoms, (vii) an aryloxyalkyl group in which the aryl moiety has from 6 to 10 carbon atoms and the alkyl moiety is straight or branched chain and has from 1 to 4 carbon atoms, (viii) a mono- or dicyclic, 5- to 10-membered hetero aryloxy group containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, nitrogen atom and sulfur atom or (ix) a mono- or dicyclic, 5- to 10-membered hetero arylthio group containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, nitrogen atom and sulfur atom,
here, the substituent xcex14 represents a group selected from the group consisting of (i) straight or branched chain alkyl groups having from 1 to 6 carbon atoms, (ii) straight or branched chain halogenated alkyl groups having from 1 to 4 carbon atoms, (iii) straight or branched chain alkoxy groups having from 1 to 4 carbon atoms, (iv) straight or branched chain halogenated alkoxy groups having from 1 to 4 carbon atoms, (v) straight or branched chain alkylthio groups having one or two carbon atoms, (vi) straight or branched chain alkylsulfonyl groups having one or two carbon atoms, (vii) halogen atoms, (viii) cyano groups or (ix) pyridyl groups, pharmacologically acceptable salts thereof or pharmacologically acceptable esters thereof;
(24) amidocarboxylic acid derivatives in which W represents a phenoxy group which may have one substituent xcex15 described below on the phenyl moiety,
here, the substituent xcex15 represents a group selected from the group consisting of (i) straight or branched chain alkyl groups having from 1 to 6 carbon atoms, (ii) straight or branched chain halogenated alkyl groups having from 1 to 4 carbon atoms, (iii) straight or branched chain alkoxy groups having from 1 to 4 carbon atoms, (iv) straight or branched chain halogenated alkoxy groups having from 1 to 4 carbon atoms, (v) straight or branched chain alkylthio groups having one or two carbon atoms, (vi) straight or branched chain alkylsulfonyl groups having from one or two carbon atoms, (vii) halogen atoms, (viii) cyano groups or (ix) pyridyl groups, pharmacologically acceptable salts thereof or pharmacologically acceptable esters thereof;
(25) amidocarboxylic acid derivatives in which W represents a phenoxy group which may have one substituent xcex16 described below on the phenyl moiety,
here, the substituent xcex16represents a group selected from the group consisting of methyl, ethyl, isopropyl, t-butyl, trifluoromethyl, methoxy and trifluoromethoxy groups, and fluorine atoms and chlorine atoms, pharmacologically acceptable salts thereof or pharmacologically acceptable esters thereof;
(26) amidocarboxylic acid derivatives in which W represents a phenoxy, methylphenoxy, ethylphenoxy, isopropylphenoxy, t-butylphenoxy, trifluoromethylphenoxy, methoxyphenoxy, trifluoromethoxyphenoxy, fluorophenoxy or chlorophenoxy group, pharmaceutically acceptable salts thereof or pharmaceutically acceptable esters thereof,
(27) amidocarboxylic acid derivatives in which X represents an aryl group having from 6 to 10 carbon atoms which may have from 1 to 3 substituents xcex17 described below or a mono- or dicyclic, 5- to 10-membered hetero aryl group containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, nitrogen atom and sulfur atom which may have from 1 to 3 substituents xcex17 described below,
here, the substituent xcex17 represents a group selected from the group consisting of (i) straight or branched chain alkyl groups having from 1 to 6 carbon atoms, (ii) straight or branched chain halogenated alkyl groups having from 1 to 4 carbon atoms, (iii) hydroxyl groups, (iv) straight or branched chain aliphatic acyloxy groups having from 1 to 5 carbon atoms, (v) straight or branched chain aliphatic acyl groups having from 1 to 5 carbon atoms, (vi) straight or branched chain alkoxy groups having from 1 to 4 carbon atoms, (vii) straight or branched chain halogenated alkoxy groups having from 1 to 4 carbon atoms, (viii) straight or branched chain alkylenedioxy groups having from 1 to 4 carbon atoms, (ix) aralkyloxy groups having from 7 to 12 carbon atoms which may have from 1 to 3 substituents xcex23 described later, (x) straight or branched chain alkylthio groups having from 1 to 4 carbon atoms, (xi) straight or branched chain alkylsulfonyl groups having from 1 to 4 carbon atoms, (xii) halogen atoms, (xiii) straight or branched chain dialkylamino groups in which each alkyl group may be the same or different and each has from 1 to 4 carbon atoms, (xiv) aralkyl groups having from 7 to 12 carbon atoms which may have from 1 to 3 substituents xcex23 described below, (xv) phenyl groups which may have from 1 to 3 substituents xcex23 described below, (xvi) phenoxy groups which may have from 1 to 3 substituents xcex23 described below, (xvii) phenylthio groups which may have from 1 to 3 substituents xcex23 described below, (xviii) phenylsulfonyl groups which may have from 1 to 3 substituentsxcex23 described below, (xix) phenylsulfonylamino groups which may have from 1 to 3 substituents xcex23 described below on the phenyl moiety (the nitrogen atom of the amino moiety may be substituted with a straight or branched chain alkyl group having from 1 to 6 carbon atoms), (xx) furyl groups, (xxi) thienyl groups, (xxii) oxazolyl groups, (xxiii) isoxazolyl groups, (xxiv) thiazolyl groups, (xxv) pyridyl groups which may have from 1 to 3 substituents xcex23 described below, (xxvi) pyridyloxy groups which may have from 1 to 3 substituents xcex23 described below, (xxvii) pyridylthio groups which may have from 1 to 3 substituents xcex23 described below, (xxviii) pyridylsulfonyl groups which may have from 1 to 3 substituents xcex23 described below, (xxix) imidazolyl groups (the nitrogen atom of the ring may be substituted with a straight or branched chain alkyl group having from 1 to 6 carbon atoms), (xxx) pyridylsulfonylamino groups which may have from 1 to 3 substituents xcex23 described below on the pyridyl moiety (the nitrogen atom of the amino moiety may be substituted with a straight or branched chain alkyl group having from 1 to 6 carbon atoms) and (xxxi) mono- or dicyclic, 5- to 10-membered saturated heterocyclic groups containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, nitrogen atom and sulfur atom,
here, the substituent xcex23 represents a group selected from the group consisting of (i) straight or branched chain alkyl groups having from 1 to 6 carbon atoms, (ii) straight or branched chain halogenated alkyl groups having from 1 to 4 carbon atoms, (iii) hydroxyl groups, (iv) straight or branched chain alkoxy groups having from 1 to 4 carbon atoms, (v) straight or branched chain halogenated alkoxy groups having from 1 to 4 carbon atoms, (vi) straight or branched chain alkylenedioxy groups having from 1 to 4 carbon atoms, (vii) straight or branched chain hydroxyalkyl groups having from 1 to 4 carbon atoms, (viii) halogen atoms, (ix) nitro groups, (x) formyl groups, (xi) cyano groups, (xii) carboxyl groups, (xiii) straight or branched chain dialkylamino groups in which each alkyl group may be the same or different and each has from 1 to 4 carbon atoms and (xiv) dialkylaminoalkyl groups in which the dialkylamino moiety has two straight or branched chain alkyl groups having from 1 to 4 carbon atoms which may be the same or different and the alkyl moiety is a straight or branched chain alkyl group having from 1 to 4 carbon atoms, pharmacologically acceptable salts thereof or pharmacologically acceptable esters thereof;
(28) amidocarboxylic acid derivatives in which X represents an aryl group having from 6 to 10 carbon atoms which may have from 1 to 3 substituents xcex18 described below or a mono- or dicyclic, 5- to 10-membered hetero aryl group containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, nitrogen atom and sulfur atom which may have from 1 to 3 substituents xcex18 described below,
here, the substituent xcex18 represents a group selected from the group consisting of (i) straight or branched chain alkyl groups having from 1 to 6 carbon atoms, (ii) straight or branched chain halogenated alkyl groups having from 1 to 4 carbon atoms, (iii) hydroxyl groups, (iv) straight or branched chain aliphatic acyloxy groups having from 1 to 5 carbon atoms, (v) straight or branched chain alkoxy groups having from 1 to 4 carbon atoms, (vi) straight or branched chain halogenated alkoxy groups having from 1 to 4 carbon atoms, (vii) straight or branched chain alkylthio groups having from 1 to 4 carbon atoms, (viii) halogen atoms, (ix) straight or branched chain dialkylamino groups in which each alkyl group may be the same or different and each has from 1 to 4 carbon atoms, (x) phenyl groups which may have from 1 to 3 substituents xcex24 described below, (xi) phenoxy groups which may have from 1 to 3 substituents xcex24 described below, (xii) phenythio groups which may have from 1 to 3 substituents xcex24 described below, (xiii) furyl groups, (xiv) thienyl groups, (xv) oxazolyl groups, (xvi) isoxazolyl groups, (xvii) thiazolyl groups, (xviii) pyridyl groups which may have from 1 to 3 substituents xcex24 described below, (xix) imidazolyl groups (the nitrogen atom of the ring may be substituted with a straight or branched chain alkyl group having from 1 to 6 carbon atoms) and (xx) mono- or dicyclic, 5- to 10-membered saturated heterocyclic groups containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, nitrogen atom and sulfur atom,
here, the substituent xcex24 represents a group selected from the group consisting of (i) straight or branched chain alkyl groups having from 1 to 6 carbon atoms, (ii) straight or branched chain halogenated alkyl groups having from 1 to 4 carbon atoms, (iii) hydroxyl groups, (iv) straight or branched chain alkoxy groups having from 1 to 4 carbon atoms, (v) straight or branched chain halogenated alkoxy groups having from 1 to 4 carbon atoms, (vi) straight or branched chain alkylenedioxy groups having from 1 to 4 carbon atoms, (vii) straight or branched chain hydroxyalkyl groups having from 1 to 4 carbon atoms, (viii) halogen atoms, (ix) nitro groups, (x) formyl groups, (xi) cyano groups, (xii) carboxyl groups, (xiii) straight or branched chain dialkylamino groups in which each alkyl group may be the same or different and each has from 1 to 4 carbon atoms and (xiv) dialkylaminoalkyl groups in which the dialkylamino moiety has two straight or branched chain alkyl groups having from 1 to 4 carbon atoms which may be the same or different and the alkyl moiety is a straight or branched chain alkyl group having from 1 to 4 carbon atoms, pharmacologically acceptable salts thereof or pharmacologically acceptable esters thereof;
(29) amidocarboxylic acid derivatives in which X represents an aryl group having from 6 to 10 carbon atoms which may have from 1 to 3 substituents xcex19 described below or a mono- or dicyclic, 5- to 10-membered hetero aryl group containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, nitrogen atom and sulfur atom which may have from 1 to 3 substituents xcex19 described below,
here, the substituent xcex19 represents a group selected from the group consisting of (i) hydroxyl groups, (ii) straight or branched chain alkoxy groups having from 1 to 4 carbon atoms, (iii) straight or branched chain halogenated alkoxy groups having from 1 to 4 carbon atoms, (iv) straight or branched chain dialkylamino groups in which each alkyl group may be the same or different and each has from 1 to 4 carbon atoms, (v) phenyl groups which may have from 1 to 3 substituents xcex25 described below, (vi) phenoxy groups which may have from 1 to 3 substituents xcex25 described below, (vii) pyridyl groups which may have from 1 to 3 substituents xcex25 described below and (viii) mono- or dicyclic, 5- to 10-membered saturated heterocyclic groups containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, nitrogen atom and sulfur atom,
here, the substituent xcex25 represents a group selected from the group consisting of (i) straight or branched chain alkyl groups having from 1 to 6 carbon atoms, (ii) straight or branched chain halogenated alkyl groups having from 1 to 4 carbon atoms, (iii) hydroxyl groups, (iv) straight or branched chain alkoxy groups having from 1 to 4 carbon atoms, (v) straight or branched chain hydroxyalkyl groups having from 1 to 4 carbon atoms, (vi) halogen atoms, (vii) nitro groups, (viii) formyl groups, (ix) carboxyl groups, (x) straight or branched chain dialkylamino groups in which each alkyl may be the same or different and each has from 1 to 4 carbon atoms and (xi) dialkylaminoalkyl groups in which the dialkylamino moiety has two straight or branched chain alkyl groups having from 1 to 4 carbon atoms which may be the same or different and the alkyl moiety is a straight or branched chain alkyl group having from 1 to 4 carbon atoms, pharmacologically acceptable salts thereof or pharmacologically acceptable esters thereof;
(30) amidocarboxylic acid derivatives in which X represents a phenyl, naphthyl, imidazolyl, oxazolyl, pyridyl, indolyl, quinolyl or isoquinolyl group which may have from 1 to 3 substituents xcex110 described below;
here, the substituent xcex110 represents the group selected from the group consisting of (i) hydroxyl groups, (ii) straight or branched chain alkoxy groups having from 1 to 4 carbon atoms, (iii) straight or branched chain halogenated alkoxy groups having from 1 to 4 carbon atoms, (iv) straight or branched chain dialkylamino groups which may be the same or different and in which each alkyl group has from 1 to 4 carbon atoms, (v) phenyl groups which may have from 1 to 3 substituents xcex26 described below, (vi) phenoxy groups which may have from 1 to 3 substituents xcex26 described below, (vii) pyridyl groups which may have from 1 to 3 substituents xcex26 described below and (viii) 5- to 10-membered saturated heterocyclic groups of one ring or two rings containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, the nitrogen atom and the sulfur atom,
here, the substituent xcex26 represents the group selected from the group consisting of (i) straight or branched chain alkyl groups having from 1 to 6 carbon atoms, (ii) straight or branched chain halogenated alkyl groups having from 1 to 4 carbon atoms, (iii) hydroxyl groups, (iv) straight or branched chain alkoxy groups having from 1 to 4 carbon atoms, (v) straight or branched chain hydroxyalkyl groups having from 1 to 4 carbon atoms, (vi) halogen atoms, (vii) nitro groups, (viii) formyl groups, (ix) carboxyl groups, (x) straight or branched chain dialkylamino groups which may be the same or different and in which each alkyl groups has from 1 to 4 carbon atoms and (xi) dialkylaminoalkyl groups in which the dialkylamino moiety has two straight or branched chain alkyl groups having from 1 to 4 carbon atoms which may be the same or different and the alkyl moiety is a straight or branched chain alkyl group having from 1 to 4 carbon atoms, pharmaceutically acceptable salts thereof or pharmaceutically acceptable esters thereof;
(31) amidocarboxylic acid derivatives in which X represents a phenyl, indolyl, pyridyl or quinolyl group, which may have from 1 to 3 substituents xcex111 described below.
here, the substituent xcex111 represents a group selected from the group consisting of (i) hydroxyl groups, (ii) straight or branched chain alkoxy groups having from 1 to 4 carbon atoms, (iii) straight or branched chain halogenated alkoxy groups having from 1 to 4 carbon atoms, (iv) straight or branched chain dialkylamino groups in which each alkyl group may be the same or different and each has from 1 to 4 carbon atoms, (v) phenyl groups which may have from 1 to 3 substituents xcex27 described below, (vi) phenoxy groups which may have from 1 to 3 substituents xcex27 described below, (vii) pyridyl groups which may have from 1 to 3 substituents xcex27 described below and (viii) mono- or dicyclic, 5- to 10-membered saturated heterocyclic groups containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, nitrogen atom and sulfur atom,
here, the substituent xcex27 represents a group selected from the group consisting of (i) straight or branched chain alkyl groups having from 1 to 6 carbon atoms, (ii) straight or branched chain halogenated alkyl groups having from 1 to 4 carbon atoms, (iii) hydroxyl groups, (iv) straight or branched chain alkoxy groups having from 1 to 4 carbon atoms, (v) straight or branched chain hydroxyalkyl groups having from 1 to 4 carbon atoms, (vi) halogen atoms, (vii) nitro groups, (viii) formyl groups, (ix) carboxyl groups, (x) straight or branched chain dialkylamino groups in which each alkyl group may be the same or different and each has from 1 to 4 carbon atoms and (xi) dialkylaminoalkyl groups in which the dialkylamino moiety has two straight or branched chain alkyl groups having from 1 to 4 carbon atoms which may be the same or different and the alkyl moiety is a straight or branched chain alkyl group having from 1 to 4 carbon atoms, pharmacologically acceptable salts thereof or pharmacologically acceptable esters thereof,
(32) amidocarboxylic acid derivatives in which X represents a phenyl group which may have one substituent xcex112 described below,
here, the substituent xcex112 represents a group selected from the group consisting of methyl, isopropyl and hydroxyl groups, fluorine atoms, chlorine atoms, diethylamino and benzyl groups, phenyl groups (the phenyl moiety may be substituted with 1 to 3 substituents, which may be the same or different, including methyl, ethyl, trifluoromethyl, hydroxyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, methylenedioxy and hydroxymethyl groups, fluorine atoms, chlorine atoms, nitro, formyl, cyano, carboxyl, dimethylamino, diethylamino and N,N-dimethylaminomethyl groups), phenoxy, phenylthio, phenylsufonyl, phenylsulfonylamino, N-methylphenylsulfonylamino and pyridyl groups (the pyridyl moiety may be substituted with a methyl, ethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy or trifluoromethoxy group, a fluorine atom, a chlorine atom, or a nitro, dimethylamino or diethylamino group), pyridyloxy, pyridylthio, pyridylsulfonyl and piperidyl groups,
or
X represents a pyridyl group which may have one substituent xcex11 described below,
here, the substituent xcex113 represents a group selected from the group consisting of methyl, isopropyl, methoxy, ethoxy, isopropoxy, 2,2,3,3-tetrafluoropropoxy and benzyloxy groups, alkylthio groups having one or two carbon atoms, alkylsulfonyl groups having one or two carbon atoms, benzyl groups, phenyl groups (the phenyl moiety may be substituted with a methyl, ethyl, trifluoromethyl, methoxy, ethoxy or isopropoxy group, a fluorine atom, a chlorine atom, or a nitro, dimethylamino or diethylamino group), phenoxy, phenylthio, phenylsufonyl, phenylsulfonylamino and N-methylphenylsulfonylamino groups, pharmacologically acceptable salts thereof or pharmacologically acceptable esters thereof;
(33) amidocarboxylic acid derivatives in which X represents a phenyl group which may have one substituent xcex112 described below,
here, the substituent xcex12 represents a group selected from the group consisting of methyl, isopropyl and hydroxyl groups, fluorine atoms, chlorine atoms, diethylamino and benzyl groups, phenyl groups (the phenyl moiety may be substituted with 1 to 3 substituents, which may be the same or different, including methyl, ethyl, trifluoromethyl, hydroxyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, methylenedioxy and hydroxymethyl groups, fluorine atoms, chlorine atoms, nitro, formyl, cyano, carboxyl, dimethylamino, diethylamino and N,N-dimethylaminomethyl groups), phenoxy, phenylthio, phenylsufonyl, phenylsulfonylamino and N-methylphenylsulfonylamino groups, pyridyl groups (the pyridyl moiety may be substituted with a methyl, ethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy, or trifluoromethoxy group, a fluorine atom, a chlorine atom, or a nitro, dimethylamino or diethylamino group), pyridyloxy, pyridylthio, pyridylsulfonyl and piperidyl groups, pharmacologically acceptable salts thereof or pharmacologically acceptable esters thereof;
(34) amidocarboxylic acid derivatives in which X represents a pyridyl group which may have one substituent xcex113 described below,
here, the substituent xcex113 represents a group selected from the group consisting of methyl, isopropyl, methoxy, ethoxy, isopropoxy, 2,2,3,3-tetrafluoropropoxy and benzyloxy groups, alkylthio groups having one or two carbon atoms, alkylsulfonyl groups having one or two carbon atoms, benzyl groups, phenyl groups (the phenyl moiety may be substituted with a methyl, ethyl, trifluoromethyl, methoxy, ethoxy or isopropoxy group, a fluorine atom, a chlorine atom, or a nitro, dimethylamino or diethylamino group), phenoxy, phenylthio, phenylsufonyl, phenylsulfonylamino and N-methylphenylsulfonylamino groups, pharmacologically acceptable salts thereof or pharmacologically acceptable esters thereof;
(35) amidocarboxylic acid derivatives in which X represents a 2,2,3,3-tetrafluoropropoxypyridyl group or a phenylpyridyl group (the phenyl moiety may be substituted with a methyl, ethyl, trifluoromethyl, methoxy, ethoxy or isopropoxy group, a fluorine atom, a chlorine atom, or a nitro, dimethylamino or diethylamino group), pharmacologically acceptable salts thereof or pharmacologically acceptable esters thereof;
(36) amidocarboxylic acid derivatives in which X represents a biphenylyl group (each phenyl moiety may be substituted with one substituent, which may be the same or different, including a methyl, trifluoromethyl, hydroxyl, methoxy or hydroxymethyl group, a fluorine atom, a chlorine atom, or a formyl, carboxyl, nitro, dimethylamino or N,N-dimethylaminomethyl group), a pyridylphenyl group (the pyridyl moiety may be substituted with one substituent including a methyl, ethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy or trifluoromethoxy group, a fluorine atom, a chlorine atom, or a nitro, dimethylamino or diethylamino group) or a phenylpyridyl group (the phenyl moiety may be substituted with one substituent including a methyl, ethyl, trifluoromethyl, methoxy, ethoxy or isopropoxy group, a fluorine atom, a chlorine atom, a nitro group or a dimethylamino group), pharmacologically acceptable salts thereof or pharmacologically acceptable esters thereof;
(37) amidocarboxylic acid derivatives in which X represents a biphenylyl, (methylphenyl)phenyl, (trifluoromethylphenyl)phenyl, (hydroxyphenyl)phenyl, (methoxyphenyl)phenyl, (hydroxymethylphenyl)phenyl, (fluorophenyl)phenyl, (chlorophenyl)phenyl, (formylphenyl)phenyl, (carboxyphenyl)phenyl, (nitrophenyl)phenyl, (dimethylaminophenyl)phenyl or (N,N-dimethylaminomethylphenyl)phenyl group, pharmacologically acceptable salts thereof or pharmacologically acceptable esters thereof;
(38) amidocarboxylic acid derivatives in which X represents a biphenylyl, (methylphenyl)phenyl, (trifluoromethylphenyl)phenyl, (methoxyphenyl)phenyl, (fluorophenyl)phenyl or (chlorophenyl)phenyl group, pharmacologically acceptable salts thereof or pharmacologically acceptable esters thereof;
(39) amidocarboxylic acid derivatives in which X represents a biphenylyl, (fluorophenyl)phenyl or (chlorophenyl)phenyl group, pharmacologically acceptable salts thereof or pharmacologically acceptable esters thereof;
(40) amidocarboxylic acid derivatives in which X represents a pyridylphenyl group (the pyridyl moiety may have one methyl, ethyl, trifluoromethyl, methoxy, ethoxy or isopropoxy group, a fluorine atom, a chlorine atom, or a nitro, dimethylamino or diethylamino group), pharmacologically acceptable salts thereof or pharmacologically acceptable esters thereof;
(41) amidocarboxylic acid derivatives in which X represents a pyridylphenyl, (methylpyridyl)phenyl, (methoxypyridyl)phenyl or (dimethylaminopyridyl)phenyl group, pharmacologically acceptable salts thereof or pharmacologically acceptable esters thereof;
(42) amidocarboxylic acid derivatives in which X represents a phenylpyridyl group (the phenyl moiety may have one methyl, ethyl, methoxy, ethoxy or isopropoxy group, a fluorine atom, a chlorine atom or a dimethylamino group), pharmacologically acceptable salts thereof or pharmacologically acceptable esters thereof;
(43) amidocarboxylic acid derivatives in which X represents a phenylpyridyl, (methoxyphenyl)pyridyl or (fluorophenyl)pyridyl group, pharmacologically acceptable salts thereof or pharmacologically acceptable esters thereof,
(44) amidocarboxylic acid derivatives in which Y represents a single bond, an oxygen atom, a sulfur atom or a group of the formula:  greater than Nxe2x80x94R5 (wherein R5 represents a hydrogen atom, a straight or branched chain alkyl group having one or two carbon atoms or a straight or branched chain aliphatic acyl group having from 2 to 5 carbon atoms), pharmacologically acceptable salts thereof or pharmacologically acceptable esters thereof;
(45) amidocarboxylic acid derivatives in which Y represents a single bond or an oxygen atom, pharmacologically acceptable salts thereof or pharmacologically acceptable esters thereof,
(46) amidocarboxylic acid derivatives in which Y represents an oxygen atom, pharmacologically acceptable salts thereof or pharmacologically acceptable esters thereof.
Further, compounds in which R1 is selected from (1) to (4), R2 is selected from (5) to (8), R3 is selected from (9) to (11), R4 is selected from (12) to (16), Z is selected from (17) to (19), W is selected from (20) to (26), X is selected from (27) to (43), and Y is selected from (44) to (46) to be combined with one another are preferable.
For example, the phenylalkylcarboxylic acid of the formula (I) includes:
(47) amidocarboxylic acid derivatives in which
R1 is a hydrogen atom, a straight or branched chain alkyl group having from 1 to 4 carbon atoms or an aralkyl group having from 7 to 9 carbon atoms;
R2 is a straight or branched chain alkylene group having from 2 to 4 carbon atoms;
R3 is a hydrogen atom, a straight or branched chain alkyl group having from 1 to 4 carbon atoms, an alkoxy group having one or two carbon atoms, an alkylthio group having one or two carbon atoms, a halogen atom, a nitro group, a hydroxyl group or a straight or branched chain aliphatic acyl group having from 1 to 5 carbon atoms;
R4 is a hydrogen atom or a straight or branched chain alkyl group having from 1 to 4 carbon atoms;
Z is a straight or branched chain alkylene group having from 1 to 4 carbon atoms;
W represents (i) a straight or branched chain alkyl group having from 1 to 6 carbon atoms, (ii) a hydroxyl group, (iii) a straight or branched chain alkoxy group having from 1 to 4 carbon atoms, (iv) a straight or branched chain alkylthio group having from 1 to 4 carbon atoms, (v) an aryl group having from 6 to 10 carbon atoms which may have from 1 to 3 substituents xcex11 described later, (vi) an aryloxy group having from 6 to 10 carbon atoms which may have from 1 to 3 substituents xcex11 described later on the aryl moiety, (vii) an arylthio group having from 6 to 10 carbon atoms which may have from 1 to 3 substituents xcex11 described later on the aryl moiety, (viii) an aralkyl group having from 7 to 12 carbon atoms which may have from 1 to 3 substituents xcex11 described later on the aryl moiety, (ix) an aralkyloxy group having from 7 to 12 carbon atoms which may have from 1 to 3 substituents xcex11 described later on the aryl moiety, (x) an aralkylthio group having from 7 to 12 carbon atoms which may have from 1 to 3 substituents xcex11 described later on the aryl moiety, (xi) an aryloxyalkyl group in which the aryl moiety is an aryl group having from 6 to 10 carbon atoms which may have from 1 to 3 substituents xcex11 described later and the alkyl moiety is a straight or branched chain alkyl group having from 1 to 4 carbon atoms, (xii) a mono- or dicyclic, 5- to 10-membered hetero aryl group containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, nitrogen atom and sulfur atom, (xiii) a mono- or dicyclic, 5- to 10-membered hetero aryloxy group containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, nitrogen atom and sulfur atom, (xiv) a mono- or dicyclic, 5- to 10-membered hetero arylthio group containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom or (xv) a mono- or dicyclic, 5- to 10-membered saturated heterocyclic group containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, nitrogen atom and sulfur atom,
here, the substituent xcex11 represents a group selected from the group consisting of (i) straight or branched chain alkyl groups having from 1 to 6 carbon atoms, (ii) straight or branched chain halogenated alkyl groups having from 1 to 4 carbon atoms, (iii) hydroxyl groups, (iv) straight or branched chain aliphatic acyloxy groups having from 1 to 5 carbon atoms, (v) straight or branched chain aliphatic acyl groups having from 1 to 5 carbon atoms, (vi) straight or branched chain alkoxy groups having from 1 to 4 carbon atoms, (vii) straight or branched chain halogenated alkoxy groups having from 1 to 4 carbon atoms, (viii) straight or branched chain alkylenedioxy groups having from 1 to 4 carbon atoms, (ix) aralkyloxy groups having from 7 to 12 carbon atoms which may have 1 to 3 substituents xcex21 described later, (x) straight or branched chain alkylthio groups having from 1 to 4 carbon atoms, (xi) straight or branched chain alkylsulfonyl groups having from 1 to 4 carbon atoms, (xii) halogen atoms, (xiii) nitro groups, (xiv) cyano groups, (xv) amino groups, (xvi) straight or branched chain monoalkylamino groups in which the alkyl moiety has from 1 to 4 carbon atoms, (xvii) straight or branched chain alkoxycarbonylamino groups in which the alkoxy moiety has from 1 to 4 carbon atoms, (xviii) aralkyloxycarbonylamino groups in which the aralkyl moiety has from 7 to 12 carbon atoms, (xix) straight or branched chain dialkylamino groups in which each alkyl group may be the same or different and each has from 1 to 4 carbon atoms, (xx) aralkyl groups having from 7 to 12 carbon atoms which may have from 1 to 3 substituents xcex21 described later on the aryl moiety, (xxi) aryl groups having from 6 to 10 carbon atoms which may have from 1 to 3 substituents xcex21 which may be the same or different, described later, (xxii) aryloxy groups having from 6 to 10 carbon atoms which may have from 1 to 3 substituents xcex21, described later on the aryl moiety, (xxiii) arylthio groups having from 6 to 10 carbon atoms which may have from 1 to 3 substituents xcex21 described later on the aryl moiety, (xxiv) arylsulfonyl groups having from 6 to 10 carbon atoms which may have from 1 to 3 substituents xcex21 described later on the aryl moiety, (xxv) arylsulfonylamino groups having from 6 to 10 carbon atoms which may have from 1 to 3 substituents xcex21 described later on the aryl moiety (the nitrogen atom of the amino moiety may be substituted with a straight or branched chain alkyl group having from 1 to 6 carbon atoms), (xxvi) mono- or dicyclic, 5- to 10-membered hetero aryl groups containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, nitrogen atom and sulfur atom which may have from 1 to 3 substituents xcex21 described later, (xxvii) mono- or dicyclic, 5- to 10-membered hetero aryloxy groups containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, nitrogen atom and sulfur atom which may have from 1 to 3 substituents xcex21 described later, (xxviii) mono- or dicyclic, 5- to 10-membered hetero arylthio groups containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, nitrogen atom and sulfur atom which may have from 1 to 3 substituents xcex21 described later, (xxix) mono- or dicyclic, 5- to 10-membered hetero arylsulfonyl groups containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, nitrogen atom and sulfur atom which may have from 1 to 3 substituents xcex21 described later, (xxx) mono- or dicyclic, 5- to 10-membered hetero arylsulfonylamino groups containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, nitrogen atom and sulfur atom which may have from 1 to 3 substituents described later on the hetero aryl moiety (the nitrogen atom of the amino moiety may be substituted with a straight or branched chain alkyl group having from 1 to 6 carbon atoms) and (xxxi) mono- or dicyclic, 5- to 10-membered saturated heterocyclic groups containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, nitrogen atom and sulfur atom,
here, the substituent xcex21 represents a group selected from the group consisting of (i) straight or branched chain alkyl groups having from 1 to 6 carbon atoms, (ii) straight or branched chain halogenated alkyl groups having from 1 to 4 carbon atoms, (iii) hydroxyl groups, (iv) straight or branched chain alkoxy groups having from 1 to 4 carbon atoms, (v) straight or branched chain halogenated alkoxy groups having from 1 to 4 carbon atoms, (vi) straight or branched chain alkylenedioxy groups having from 1 to 4 carbon atoms, (vii) straight or branched chain hydroxyalkyl groups having from 1 to 4 carbon atoms, (viii) halogen atoms, (ix) nitro groups, (x) formyl groups, (xi) cyano groups, (xii) carboxyl groups, (xiii) amino groups, (xiv) straight or branched chain monoalkylamino groups in which the alkyl moiety has from 1 to 4 carbon atoms, (xv) straight or branched chain dialkylamino groups in which each alkyl moiety may be the same or different and each has from 1 to 4 carbon atoms, (xvi) straight or branched chain aminoalkyl groups having from 1 to 4 carbon atoms, (xvii) monoalkylaminoalkyl groups in which the monoalkylamino moiety has one straight or branched chain alkyl group having from 1 to 4 carbon atoms and the alkyl moiety is a straight or branched chain alkyl group having from 1 to 4 carbon atoms, (xxviii) dialkylaminoalkyl groups in which the dialkylamino moiety has two straight or branched chain alkyl groups having from 1 to 4 carbon atoms which may be the same or different and the alkyl moiety is a straight or branched chain alkyl group having from 1 to 4 carbon atoms, (xix) straight or branched chain alkoxycarbonylamino groups in which the alkoxy moiety is a straight or branched chain alkoxy group having from 1 to 4 carbon atoms and (xx) aralkyloxycarbonylamino groups in which the aryl moiety has from 6 to 10 carbon atoms and the alkyl moiety has from 1 to 4 carbon atoms;
X represents an aryl group having from 6 to 10 carbon atoms which may have from 1 to 3 substituents xcex17 described later or a mono- or dicyclic, 5- to 10-membered hetero aryl group containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, nitrogen atom and sulfur atom which may have from 1 to 3 substituents xcex17 described below,
here, the substituent xcex17 represents a group selected from the group consisting of (i) straight or branched chain alkyl groups having from 1 to 6 carbon atoms, (ii) straight or branched chain halogenated alkyl groups having from 1 to 4 carbon atoms, (iii) hydroxyl groups, (iv) straight or branched chain aliphatic acyloxy groups having from 1 to 5 carbon atoms, (v) straight or branched chain aliphatic acyl groups having from 1 to 5 carbon atoms, (vi) straight or branched chain alkoxy groups having from 1 to 4 carbon atoms, (vii) straight or branched chain halogenated alkoxy groups having from 1 to 4 carbon atoms, (viii) straight or branched chain alkylenedioxy groups having from 1 to 4 carbon atoms, (ix) aralkyloxy groups having from 7 to 12 carbon atoms which may have from 1 to 3 substituents xcex23 described later, (x) straight or branched chain alkylthio groups having from 1 to 4 carbon atoms, (xi) straight or branched chain alkylsulfonyl groups having from 1 to 4 carbon atoms, (xii) halogen atoms, (xiii) straight or branched chain dialkylamino groups in which each alkyl group may be the same or different and each has from 1 to 4 carbon atoms, (xiv) aralkyl groups having from 7 to 12 carbon atoms which may have from 1 to 3 substituents xcex23 described later, (xv) phenyl groups which may have from 1 to 3 substituents xcex23 described later, (xvi) phenoxy groups which may have from 1 to 3 substituents xcex23 described later, (xvii) phenylthio groups which may have from 1 to 3 substituents xcex23 described later, (xviii) phenylsulfonyl groups which may have from 1 to 3 substituents xcex23 described later on the phenyl moiety, (xix) phenylsulfonylamino groups which may have from 1 to 3 substituents xcex23 described later on the phenyl moiety (the nitrogen atom of the amino moiety may be substituted with a straight or branched chain alkyl group having from 1 to 6 carbon atoms), (xx) furyl groups, (xxi) thienyl groups, (xxii) oxazolyl groups, (xxiii) isoxazolyl groups, (xxiv) thiazolyl groups, (xxv) pyridyl groups which may have from 1 to 3 substituents xcex23 described later, (xxvi) pyridyloxy groups which may have from 1 to 3 substituents xcex23 described later, (xxvii) pyridylthio groups which may have from 1 to 3 substituents xcex23 described later, (xxviii) pyridylsulfonyl groups which may have from 1 to 3 substituents xcex23 described later, (xxix) imidazolyl groups (the nitrogen atom of the ring may be substituted with a straight or branched chain alkyl group having from 1 to 6 carbon atoms), (xxx) pyridylsulfonylamino groups which may have from 1 to 3 substituents xcex23 described later on the pyridyl moiety (the nitrogen atom of the amino moiety may be substituted with a straight or branched chain alkyl group having from 1 to 6 carbon atoms) and (xxxi) mono- or dicyclic, 5- to 10-membered saturated heterocyclic groups containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, nitrogen atom and sulfur atom,
here, the substituent xcex23 represents a group selected from the group consisting of (i) straight or branched chain alkyl groups having from 1 to 6 carbon atoms, (ii) straight or branched chain halogenated alkyl groups having from 1 to 4 carbon atoms, (iii) hydroxyl groups, (iv) straight or branched chain alkoxy groups having from 1 to 4 carbon atoms, (v) straight or branched chain halogenated alkoxy groups having from I to 4 carbon atoms, (vi) straight or branched chain alkylenedioxy groups having from 1 to 4 carbon atoms, (vii) straight or branched chain hydroxyalkyl groups having from 1 to 4 carbon atoms, (viii) halogen atoms, (ix) nitro groups, (x) formyl groups, (xi) cyano groups, (xii) carboxyl groups, (xiii) straight or branched chain dialkylamino group in which each alkyl group may be the same or different and each has from 1 to 4 carbon atoms and (xiv) dialkylaminoalkyl groups in which the dialkylamino moiety has two straight or branched chain alkyl groups having from 1 to 4 carbon atoms which may be the same or different and the alkyl moiety is a straight or branched chain alkyl group having from 1 to 4 carbon atoms; and
Y is a single bond or an oxygen atom, pharmacologically acceptable salts thereof or pharmacologically acceptable esters thereof;
(48) amidocarboxylic acid derivatives in which
R1 is a hydrogen atom, a straight or branched chain alkyl group having from 1 to 4 carbon atoms or an aralkyl group having from 7 to 9 carbon atoms;
R2 is a straight or branched chain alkylene group having from 2 to 4 carbon atoms;
R3 is a hydrogen atom, a halogen atom or a nitro group;
R4 is a hydrogen atom or a straight or branched chain alkyl group having from 1 to 4 carbon atoms;
Z is a methylene group;
W represents (i) a straight or branched chain alkyl group having from 1 to 6 carbon atoms, (ii) a hydroxyl group, (iii) a straight or branched chain alkoxy group having from 1 to 4 carbon atoms, (iv) a straight or branched chain alkylthio group having from 1 to 4 carbon atoms, (v) an aryl group having from 6 to 10 carbon atoms which may have from 1 to 3 substituents xcex12 described later, (vi) an aryloxy group having from 6 to 10 carbon atoms which may have from 1 to 3 substituents xcex12 described later on the aryl moiety, (vii) an arylthio group having from 6 to 10 carbon atoms which may have from 1 to 3 substituents xcex12 described later on the aryl moiety, (viii) an aralkyl group having from 7 to 12 carbon atoms which may have from 1 to 3 substituents xcex12 described later on the aryl moiety, (ix) an aralkyloxy group having from 7 to 12 carbon atoms which may have from 1 to 3 substituents xcex12 described later on the aryl moiety, (x) an aralkylthio group having from 7 to 12 carbon atoms which may have from 1 to 3 substituents xcex12 described later on the aryl moiety, (xi) an aryloxyalkyl group in which the aryl moiety is an aryl group having from 6 to 10 carbon atoms which may have from 1 to 3 substituents xcex12 described later and the alkyl moiety is a straight or branched chain alkyl having from 1 to 4 carbon atoms, (xii) a mono- or dicyclic, 5- to 10-membered hetero aryloxy group containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, nitrogen atom and sulfur atom or (xiii) a mono- or dicyclic, 5- to 10-membered hetero arylthio group containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, nitrogen atom and sulfur atom,
here, the substituent xcex12 represents a group selected from the group consisting of (i) straight or branched chain alkyl groups having from 1 to 6 carbon atoms, (ii) straight or branched chain halogenated alkyl groups having from 1 to 4 carbon atoms, (iii) hydroxyl groups, (iv) straight or branched chain aliphatic acyloxy groups having from 1 to 5 carbon atoms, (v) straight or branched chain alkoxy groups having from 1 to 4 carbon atoms, (vi) straight or branched chain halogenated alkoxy groups having from 1 to 4 carbon atoms, (vii) straight or branched chain alkylthio groups having from 1 to 4 carbon atoms, (viii) straight or branched chain alkylsulfonyl groups having from 1 to 4 carbon atoms, (ix) halogen atoms, (x) nitro groups, (xi) cyano groups, (xii) straight or branched chain dialkylamino groups in which each alkyl group may be the same or different and each has from 1 to 4 carbon atoms, (xiii) aryl groups having from 6 to 10 carbon atoms which may have from 1 to 3 substituents xcex22, which may be the same or different, described later, (xiv) aryloxy groups having from 6 to 10 carbon atoms which may have from 1 to 3 substituents xcex22 described later on the aryl moiety, (xv) arylthio groups having from 6 to 10 carbon atoms which may have from 1 to 3 substituents xcex22 described later on the aryl moiety, (xvi) mono- or dicyclic, 5- to 10-membered hetero aryl groups containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, nitrogen atom and sulfur atom which may have from 1 to 3 substituents xcex22 described later, (xvii) mono- or dicyclic, 5- to 10-membered hetero aryloxy groups containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, nitrogen atom and sulfur atom which may have from 1 to 3 substituents xcex22 described later, (xviii) mono- or dicyclic, 5- to 10-membered hetero arylthio groups containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, nitrogen atom and sulfur atom which may have from 1 to 3 substituents xcex22 described later and (xix) mono- or dicyclic, 5- to 10-membered saturated heterocyclic groups containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, nitrogen atom and sulfur atom,
here, the substituent xcex22 represents a group selected from the group consisting of (i) straight or branched chain alkyl groups having from 1 to 6 carbon atoms, (ii) straight or branched chain halogenated alkyl groups having from 1 to 4 carbon atoms, (iii) straight or branched chain alkoxy groups having from 1 to 4 carbon atoms, (iv) straight or branched chain hydroxyalkyl groups having from 1 to 4 carbon atoms, (v) halogen atoms, (vi) nitro groups, (vii) formyl groups, (viii) carboxyl groups, (ix) straight or branched chain dialkylamino groups in which each alkyl group may be the same or different and each has from 1 to 4 carbon atoms and (x) dialkylaminoalkyl groups in which the dialkylamino moiety has two straight or branched chain alkyl groups having from 1 to 4 carbon atoms which may be the same or different and the alkyl moiety is a straight or branched chain alkyl group having from 1 to 4 carbon atoms;
X represents an aryl group having from 6 to 10 carbon atoms which may have from 1 to 3 substituents xcex18 described below or a mono- or dicyclic, 5- to 10-membered hetero aryl group containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, nitrogen atom and sulfur atom which may have from 1 to 3 substituents xcex18 described below,
here, the substituent xcex18 represents a group selected from the group consisting of (i) straight or branched chain alkyl groups having from 1 to 6 carbon atoms, (ii) straight or branched chain halogenated alkyl groups having from 1 to 4 carbon atoms, (iii) hydroxyl groups, (iv) straight or branched chain aliphatic acyloxy groups having from 1 to 5 carbon atoms, (v) straight or branched chain alkoxy groups having from 1 to 4 carbon atoms, (vi) straight or branched chain halogenated alkoxy groups having from 1 to 4 carbon atoms, (vii) straight or branched chain alkylthio groups having from 1 to 4 carbon atoms, (viii) halogen atoms, (ix) straight or branched chain dialkylamino groups in which each alkyl group may be the same or different and each has from 1 to 4 carbon atoms, (x) phenyl groups which may have from 1 to 3 substituents xcex24 described later, (xi) phenoxy groups which may have from 1 to 3 substituents xcex24 described later, (xii) phenylthio groups which may have from 1 to 3 substituents 4 described later, (xiii) furyl groups, (xiv) thienyl groups, (xv) oxazolyl groups, (xvi) isoxazolyl groups, (xvii) thiazolyl groups, (xviii) pyridyl groups which may have from 1 to 3 substituents xcex24 described later, (xix) imidazolyl groups (the nitrogen atom of the ring may be substituted with a straight or branched chain alkyl group having from 1 to 6 carbon atoms) and (xx) mono- or dicyclic, 5- to 10-membered saturated heterocyclic groups containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, nitrogen atom and sulfur atom,
here, the substituent xcex24 represents a group selected from the group consisting of (i) straight or branched chain alkyl groups having from 1 to 6 carbon atoms, (ii) straight or branched chain halogenated alkyl groups having from 1 to 4 carbon atoms, (iii) hydroxyl groups, (iv) straight or branched chain alkoxy groups having from 1 to 4 carbon atoms, (v) straight or branched chain halogenated alkoxy groups having from 1 to 4 carbon atoms, (vi) straight or branched chain alkylenedioxy groups having from 1 to 4 carbon atoms, (vii) straight or branched chain hydroxyalkyl groups having from 1 to 4 carbon atoms, (viii) halogen atoms, (ix) nitro groups, (x) formyl groups, (xi) cyano groups, (xii) carboxyl groups, (xiii) straight or branched chain dialkylamino groups in which each alkyl group may be the same or different and have from 1 to 4 carbon atoms and (xiv) dialkylamninoalkyl groups in which the dialkylamino moiety has two straight or branched chain alkyl groups having from 1 to 4 carbon atoms which may be the same or different and the alkyl moiety is a straight or branched chain alkyl group having from 1 to 4 carbon atoms; and
Y is an oxygen atom, pharmacologically acceptable salts thereof or pharmacologically acceptable esters thereof;
(49) amidocarboxylic acid derivatives in which
R1 is a hydrogen atom, a straight or branched chain alkyl group having from 1 to 4 carbon atoms or an aralkyl group having from 7 to 9 carbon atoms;
R2 is a straight or branched chain alkylene group having from 2 to 4 carbon atoms;
R3 is a hydrogen atom, a halogen atom or a nitro group;
R4 is a hydrogen atom or a straight or branched chain alkyl group having from 1 to 4 carbon atoms;
Z is a methylene group;
W represents (i) a straight or branched chain alkyl group having from 1 to 6 carbon atoms, (ii) a straight or branched chain alkoxy group having from 1 to 4 carbon atoms, (iii) an aryloxy group having from 6 to 10 carbon atoms which may have from 1 to 3 substituents xcex13 described later on the aryl moiety, (iv) an arylthio group having from 6 to 10 carbon atoms which may have from 1 to 3 substituents xcex13 described later on the aryl moiety, (v) an aralkyl group having from 7 to 12 carbon atoms which may have from 1 to 3 substituents xcex13 described later on the aryl moiety, (vi) an aralkyloxy group having from 7 to 12 carbon atoms which may have from 1 to 3 substituents xcex13 described later on the aryl moiety, (vii) an aryloxyalkyl group in which the aryl moiety is an aryl group having from 6 to 10 carbon atoms which may have from 1 to 3 substituents xcex13 described later and the alkyl moiety is a straight or branched chain alkyl group having from 1 to 4 carbon atoms, (viii) a mono- or dicyclic, 5- to 10-membered hetero aryloxy group containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, nitrogen atom and sulfur atom or (ix) a mono- or dicyclic, 5- to 10-membered hetero arylthio group containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, nitrogen atom and sulfur atom,
here, the substituent xcex13 represents a group selected from the group consisting of (i) straight or branched chain alkyl groups having from 1 to 6 carbon atoms, (ii) straight or branched chain halogenated alkyl groups having from 1 to 4 carbon atoms, (iii) straight or branched chain alkoxy groups having from 1 to 4 carbon atoms, (iv) straight or branched chain halogenated alkoxy groups having from 1 to 4 carbon atoms, (v) straight or branched chain alkylthio groups having from 1 to 4 carbon atoms, (vi) straight or branched chain alkylsulfonyl groups having from 1 to 4 carbon atoms, (vii) halogen atoms, (viii) cyano groups and (ix) pyridyl groups;
X represents an aryl group having from 6 to 10 carbon atoms which may have from 1 to 3 substituents xcex19 described below or a mono- or dicyclic, 5- to 10-membered hetero aryl group containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, nitrogen atom and sulfur atom which may have from 1 to 3 substituents xcex19 described below,
here, the substituent xcex19 represents a group selected from the group consisting of (i) hydroxyl groups, (ii) straight or branched chain alkoxy groups having from 1 to 4 carbon atoms, (iii) straight or branched chain halogenated alkoxy groups having from 1 to 4 carbon atoms, (iv) straight or branched chain dialkylamino groups in which each alkyl group may be the same or different and have from 1 to 4 carbon atoms, (v) phenyl groups which may have from 1 to 3 substituents xcex25 described below, (vi) phenoxy groups which may have from 1 to 3 substituents xcex25 described below, (vii) pyridyl groups which may have from 1 to 3 substituents xcex25 described below and (viii) mono- or dicyclic, 5- to 10-membered saturated heterocyclic groups containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, nitrogen atom and sulfur atom,
here, the substituent xcex25 represents a group selected from the group consisting of (i) straight or branched chain alkyl groups having from 1 to 6 carbon atoms, (ii) straight or branched chain halogenated alkyl groups having from 1 to 4 carbon atoms, (iii) hydroxyl groups, (iv) straight or branched chain alkoxy groups having from 1 to 4 carbon atoms, (v) straight or branched chain hydroxyalkyl groups having from 1 to 4 carbon atoms, (vi) halogen atoms, (vii) nitro groups, (viii) formyl groups, (ix) carboxyl groups, (x) straight or branched chain dialkylamino groups in which each alkyl group may be the same or different and have from 1 to 4 carbon atoms and (xi) dialkylaminoalkyl groups in which the dialkylamino moiety has two straight or branched chain alkyl groups having from 1 to 4 carbon atoms which may be the same or different and the alkyl moiety is a straight or branched chain alkyl group having from 1 to 4 carbon atoms; and
Y is an oxygen atom, pharmacologically acceptable salts thereof or pharmacologically acceptable esters thereof;
(50) amidocarboxylic acid derivatives in which
R1 is a hydrogen atom;
R2 is an ethylene group;
R3 is a hydrogen atom;
R4 is a hydrogen atom;
Z is a methylene group;
W is a phenoxy group which may have one substituent xcex15 described below on the phenyl moiety,
here, the substituent xcex15 represents a group selected from the group consisting of (i) straight or branched chain alkyl groups having from 1 to 6 carbon atoms, (ii) straight or branched chain halogenated alkyl groups having from 1 to 4 carbon atoms, (iii) straight or branched chain alkoxy groups having from 1 to 4 carbon atoms, (iv) straight or branched chain halogenated alkoxy groups having from 1 to 4 carbon atoms, (v) straight or branched chain alkylthio groups having one or two carbon atoms, (vi) straight or branched chain alkylsulfonyl groups having one or two carbon atoms, (vii) halogen atoms, (viii) cyano groups and (ix) pyridyl groups;
X represents a phenyl group which may have one substituent xcex112 described below,
here, the substituent xcex112 represents a group selected from the group consisting of methyl, isopropyl and hydroxyl groups, fluorine atoms, chlorine atoms, diethylamino and benzyl groups, phenyl groups (the phenyl moiety may be substituted with 1 to 3 substituents, which may be the same or different, including methyl, ethyl, trifluoromethyl, hydroxyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, methylenedioxy and hydroxymethyl groups, fluorine atoms, chlorine atoms and nitro, formyl, cyano, carboxyl, dimethylamino, diethylamino and N,N-dimethylaminomethyl groups), phenoxy, phenylthio, phenylsulfonyl, phenylsulfonylamino and N-methylphenylsulfonylamino groups, pyridyl groups (the pyridyl moiety may be substituted with a methyl, ethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy or trifluoromethoxy group, a fluorine atom, a chlorine atom or a nitro, dimethylamino or diethylamino group), pyridyloxy, pyridyithio, pyridylsulfonyl and piperidyl groups, or
X represents a pyridyl group which may have one substituent xcex113 described below,
here, the substituent xcex113 represents a group selected from the group consisting of methyl, isopropyl, methoxy, ethoxy, isopropoxy, 2,2,3,3-tetrafluoropropoxy and benzyloxy groups, alkylthio groups having one or two carbon atoms, alkylsulfonyl groups having one or two carbon atoms, benzyl groups, phenyl groups (the phenyl moiety may be substituted with a methyl, ethyl, trifluoromethyl, methoxy, ethoxy or isopropoxy group, a fluorine atom, a chlorine atom, or a nitro, dimethylarnino or diethylamino group), phenoxy, phenylthio, phenylsulfonyl, phenylsulfonylamino and N-methylphenylsulfonylamino groups; and
Y is an oxygen atom, pharmacologically acceptable salts thereof or pharmacologically acceptable esters thereof; and
(51) amidocarboxylic acid derivatives in which
R1 is a hydrogen atom;
R2 is an ethylene group;
R3 is a hydrogen atom;
R4 is a hydrogen atom;
Z is a methylene group;
W is a phenoxy group which may have one substituent xcex16 described below on the phenyl moiety,
here, the substituent xcex16 represents a group selected from the group consisting of methyl, ethyl, isopropyl, t-butyl, trifluoromethyl, methoxy and trifluoromethoxy groups, and fluorine atoms and chlorine atoms;
X is a biphenylyl group (substituents of each phenyl moiety may be the same or different and one of them may be substituted with a methyl, trifluoromethyl, hydroxyl, methoxy or hydroxymethyl group, a fluorine atom, a chlorine atom, or a formyl, carboxyl, nitro, dimethylamino or N,N-dimethylaminomethyl group), a pyridylphenyl group (the pyridyl moiety may be substituted with one substituent chosen from methyl, ethyl, trifluoromethyl, methoxy, ethoxy, isopropoxy and trifluoromethoxy groups, fluorine atoms, chlorine atoms, and nitro, dimethylamino and diethylamino groups) or a phenylpyridyl group (the phenyl moiety may be substituted with one substituent chosen from methyl, ethyl, trifluoromethyl, methoxy, ethoxy and isopropoxy groups, fluorine atoms, chlorine atoms, and nitro and dimethylamino groups); and
Y is an oxygen atom, pharmacologically acceptable salts thereof or pharmacologically acceptable esters thereof.
Further, a compound having the following combination is preferable.
(52) amidocarboxylic acid derivatives in which
R1 is a hydrogen atom or a straight or branched chain alkyl group having from 1 to 6 carbon atoms;
R2 is a straight or branched chain alkylene group having from 1 to 6 carbon atoms;
R3 is (i) a hydrogen atom, (ii) a straight or branched chain alkyl group having from 1 to 6 carbon atoms, (iii) a straight or branched chain alkoxy group having from 1 to 4 carbon atoms, (iv) a straight or branched chain alkylthio group having from 1 to 4 carbon atoms, (v) a halogen atom, (vi) a nitro group, (vii) a straight or branched chain dialkylamino group in which each alkyl group may be the same or different and have from 1 to 4 carbon atoms, (viii) an aryl group having from 6 to 10 carbon atoms which may have from 1 to 3 substituents xcex1 described later or (ix) an aralkyl group having from 7 to 12 carbon atoms which may have from 1 to 3 substituents xcex1 described later on the aryl moiety;
R4 is a hydrogen atom or a straight or branched chain alkyl group having from 1 to 6 carbon atoms;
Z is a straight or branched chain alkylene group having from 1 to 4 carbon atoms;
W is an ethyl, propyl, butyl, pentyl, methoxy, ethoxy, propoxy, isopropoxy, methylthio, ethylthio, propylthio, isopropylthio, phenoxy, 4-methylphenoxy, 4-ethylphenoxy, 4-isopropylphenoxy, 4-methoxyphenoxy, 4-chlorophenoxy, phenylthio, benzyl, phenethyl, 3-phenylpropyl or 4-phenylbutyl group;
X represents an aryl group having from 6 to 10 carbon atoms which may have from 1 to 3 substituents xcex1 described later or a mono- or dicyclic, 5- to 10-membered hetero aryl group containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, nitrogen atom and sulfur atom which may have from 1 to 3 substituents xcex1 described below,
here, the substituent xcex1 represents a group selected from the group consisting of (i) straight or branched chain alkyl groups having from 1 to 6 carbon atoms, (ii) straight or branched chain halogenated alkyl groups having from 1 to 4 carbon atoms, (iii) hydroxyl groups, (iv) straight or branched chain aliphatic acyloxy groups having from 1 to 5 carbon atoms, (v) straight or branched chain alkoxy groups having from 1 to 4 carbon atoms, (vi) straight or branched chain alkylenedioxy groups having from 1 to 4 carbon atoms, (vii) aralkyloxy groups having from 7 to 12 carbon atoms, (viii) straight or branched chain alkylthio groups having from 1 to 4 carbon atoms, (ix) straight or branched chain alkylsulfonyl groups having from 1 to 4 carbon atoms, (x) halogen atoms, (xi) nitro groups, (xii) straight or branched chain dialkylamino groups in which each alkyl group may be the same or different and have from 1 to 4 carbon atoms, (xiii) aralkyl groups having from 7 to 12 carbon atoms, (xiv) aryl groups having from 6 to 10 carbon atoms (the aryl moiety may be substituted with a straight or branched chain alkyl group having from 1 to 6 carbon atoms, a straight or branched chain halogenated alkyl group having from 1 to 4 carbon atoms, a straight or branched chain alkoxy group having from 1 to 4 carbon atoms, a halogen atom or a straight or branched chain alkylenedioxy group having from 1 to 4 carbon atoms), (xv) aryloxy groups having from 6 to 10 carbon atoms (the aryl moiety may be substituted with a straight or branched chain alkyl group having from 1 to 6 carbon atoms, a straight or branched chain halogenated alkyl group having from 1 to 4 carbon atoms, a straight or branched chain alkoxy group having from 1 to 4 carbon atoms, a halogen atom or a straight or branched chain alkylenedioxy group having from 1 to 4 carbon atoms), (xvi) arylthio groups having from 6 to 10 carbon atoms (the aryl moiety may be substituted with a straight or branched chain alkyl having from 1 to 6 carbon atoms, a straight or branched chain halogenated alkyl group having from 1 to 4 carbon atoms, a straight or branched chain alkoxy group having from 1 to 4 carbon atoms, a halogen atom or a straight or branched chain alkylenedioxy group having from 1 to 4 carbon atoms), (xvii) arylsulfonyl groups having from 6 to 10 carbon atoms (the aryl moiety may be substituted with a straight or branched chain alkyl group having from 1 to 6 carbon atoms, a straight or branched chain halogenated alkyl group having from 1 to 4 carbon atoms, a straight or branched chain alkoxy group having from 1 to 4 carbon atoms, a halogen atom or a straight or branched chain alkylenedioxy group having from 1 to 4 carbon atoms), (xviii) arylsulfonylamino groups having from 6 to 10 carbon atoms (the aryl moiety may be substituted with a straight or branched chain alkyl group having from 1 to 6 carbon atoms, a straight or branched chain halogenated alkyl group having from 1 to 4 carbon atoms, a straight or branched chain alkoxy group having from 1 to 4 carbon atoms, a halogen atom or a straight or branched chain alkylenedioxy group having from 1 to 4 carbon atoms and the nitrogen atom of the amino moiety may be substituted with a straight or branched chain alkyl group having from 1 to 6 carbon atoms), (xix) mono- or dicyclic, 5- to 10-membered hetero aryl groups containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, nitrogen atom and sulfur atom, (xx) mono- or dicyclic, 5- to 10-membered hetero aryloxy groups containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, nitrogen atom and sulfur atom, (xxi) mono- or dicyclic, 5- to 10-membered hetero arylthio groups containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, nitrogen atom and sulfur atom, (xxii) mono- or dicyclic, 5- to 10-membered hetero arylsulfonyl groups containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, nitrogen atom and sulfur atom and (xxiii) mono- or dicyclic, 5- to 10-membered hetero arylsulfonylamino groups containing from 1 to 4 hetero atoms selected from the group consisting of an oxygen atom, nitrogen atom and sulfur atom (the nitrogen atom of the amino moiety may be substituted with a straight or branched chain alkyl group having from 1 to 6 carbon atoms); and
Y is a single bond, an oxygen atom, a sulfur atom or a group of the formula:  greater than Nxe2x80x94R5 (wherein R5 represents a hydrogen atom, a straight or branched chain alkyl group having from 1 to 6 carbon atoms, a straight or branched chain aliphatic acyl group having from 1 to 8 carbon atoms or an aromatic acyl group having from 7 to 11 carbon atoms), pharmacologically acceptable salts thereof or pharmacologically acceptable esters thereof.
Exemplified compounds of the amidocarboxylic acid of formula (I), pharmacologically acceptable salts thereof or pharmacologically acceptable esters thereof of the present invention are illustrated in the following Tables.
Incidentally, the following abbreviation is used in Table 1 to Table 155. Ex.No.Comp: Exemplification Number Compound
Ac: acetyl, Bu: butyl, tBu: t-butyl, Bimid: benzimidazolyl Boxa: benzoxazolyl, Bthiz: benzothiazolyl, Bz: benzyl, Dea: diethylamino, Dma: dimethylamino, Dmam: dimethylaminomethyl, Et: ethyl, Fur: furyl, Hex: hexyl, Imid: imidazolyl, Ind: indolyl, Isox: isoxazolyl, MdO: methylenedioxy, Me: methyl, Mor: morpholino, Np: naphthyl, Oxa: oxazolyl, Pen: pentyl, Ph: phenyl, Pip: piperidinyl, PPr: 3-phenylpropyl, Pr: propyl, iPr: isopropyl, Pym: pyrimidinyl, Pyr: pyridyl, Pyrd: pyrrolidinyl, Pyrr: pyrrolyl, Pyza: pyrazolyl, Quin: quinolyl, iQuin: isoquinolyl, Tfp: 2,2,3,3-tetrafluoropropyl, Thi: thienyl, Thiz: thiazolyl.
It should be noted that the compounds of Table 1 to Table 145 have the following formula (Ia) and the compounds of Table 146 to Table 155 have the following formula (Ib).
In the above tables,
(1) the following compounds are preferred: compounds Nos. 1-15, 1-16, 1-17, 1-19, 1-21, 1-35, 1-37, 1-39, 1-90, 1-92, 1-93, 1-94, 1-95, 1-96, 1-97, 1-98, 1-99, 1-100, 1-101, 1-102, 1-103, 1-104,1-105, 1-106, 1-107, 1-108, 1-109, 1-110, 1-111, 1-112, 1-143, 1-150, 1-179, 1-189, 1-190, 1-191, 1-204, 1-205, 1-206, 1-207, 1-208, 1-209, 1-210, 1-211, 1-212, 1-213, 1-214, 1-215, 1-216, 1-217, 1-218, 1-219, 1-220, 1-221, 1-222, 1-223, 1-224, 1-225, 1-226, 1-227, 1-228, 1-229, 1-230, 1-231, 1-232, 1-233, 1-234, 1-235, 1-236, 1-242, 1-243, 1-244, 1-246, 3-15, 3-16, 3-17, 3-19, 3-21, 3-35, 3-37, 3-39, 3-90, 3-92, 3-93, 3-94, 3-95, 3-96, 3-97, 3-98, 3-99, 3-100, 3-101, 3-102, 3-103, 3-104, 3-105, 3-106, 3-107, 3-108, 3-109, 3-110, 3-111, 3-112, 3-143, 3-150, 3-179, 3-189, 3-190, 3-191, 3-204, 3-205, 3-206, 3-207, 3-208, 3-209, 3-210, 3-211, 3-212, 3-213, 3-214, 3-215, 3-216, 3-217, 3-218, 3-219, 3-220, 3-221, 3-222, 3-223, 3-224, 3-225, 3-226, 3-227, 3-228, 3-229, 3-230, 3-231, 3-232, 3-233, 3-234, 3-235, 3-236, 3-242, 3-243, 3-244, 3-246, 4-15, 4-16, 4-17, 4-19, 4-21, 4-35, 4-37, 4-39, 4-90, 4-92, 4-93, 4-94, 4-95, 4-96, 4-97, 4-98, 4-99, 4-100, 4-101, 4-102, 4-103, 4-104, 4-105, 4-106, 4-107, 4-108, 4-109, 4-110, 4-111, 4-112, 4-143, 4-150, 4-179, 4-189, 4-190, 4-191, 4-193, 4-204, 4-205, 4-206, 4-207, 4-208, 4-209, 4-210, 4-211, 4-212, 4-213, 4-214, 4-215, 4-216, 4-217, 4-218, 4-219, 4-220, 4-221, 4-222, 4-223, 4-224, 4-225, 4-226, 4-227, 4-228, 4-229, 4-230, 4-231, 4-232, 4-233, 4-234, 4-235, 4-236, 4-242, 4-243, 4-244, 4-246, 5-15, 5-16, 5-17, 5-19, 5-21, 5-35, 5-37, 5-39, 5-90, 5-92, 5-93, 5-94, 5-95, 5-96, 5-97, 5-98, 5-99, 5-100, 5-101, 5-102, 5-103, 5-104, 5-105, 5-106, 5-107, 5-108, 5-109, 5-110, 5-111, 5-112, 6-15, 6-16, 6-17, 6-19, 6-21, 6-35, 6-37, 6-39, 6-90, 6-92, 6-93, 6-94, 6-95, 6-96, 6-97, 6-98, 6-99, 6-100, 6-101, 6-102, 6-103, 6-104, 6-105, 6-106, 6-107, 6-108, 6-109, 6-110, 6-111, 6-112, 6-143, 6-150, 6-179, 6-189, 6-190, 6-191, 6-204, 6-205, 6-206, 6-207, 6-208, 6-209, 6-210, 6-211, 6-212, 6-213, 6-214, 6-215, 6-216, 6-217, 6-218, 6-219, 6-220, 6-221, 6-222, 6-223, 6-224, 6-225, 6-226, 6-227, 6-228, 6-229, 6-230, 6-231, 6-232, 6-233, 6-234, 6-235, 6-236, 6-242, 6-243, 6-244, 6-246, 7-15, 7-16, 7-17, 7-19, 7-21, 7-35, 7-37, 7-39, 7-90, 7-92, 7-93, 7-94, 7-95, 7-96, 7-97, 7-98, 7-99, 7-100, 7-101, 7-102, 7-103, 7-104, 7-105, 7-106, 7-107, 7-108, 7-109, 7-110, 7-111, 7-112, 7-143, 7-150, 7-179, 7-189, 7-190, 7-191, 7-204, 7-205, 7-206, 7-207, 7-208, 7-209, 7-210, 7-211, 7-212, 7-213, 7-214, 7-215, 7-216, 7-217, 7-218, 7-219, 7-220, 7-221, 7-222, 7-223, 7-224, 7-225, 7-226, 7-227, 7-228, 7-229, 7-230, 7-231, 7-232, 7-233, 7-234, 7-235, 7-236, 7-242, 7-243, 7-244, 7-246, 8-15, 8-16, 8-17, 8-19, 8-21, 8-35, 8-37, 8-39, 8-90, 8-92, 8-93, 8-94, 8-95, 8-96, 8-97, 8-98, 8-99, 8-100, 8-101, 8-102, 8-103, 8-104, 8-105, 8-106, 8-107, 8-1088-109, 8-110, 8-111, 8-112, 8-143, 8-150, 8-179, 8-189, 8-190, 8-191, 8-204, 8-205, 8-206, 8-207, 8-208, 8-209, 8-210, 8-211, 8-212, 8-213, 8-214, 8-215, 8-216, 8-217, 8-218, 8-219, 8-220, 8-221, 8-222, 8-223, 8-224, 8-225, 8-226, 8-227, 8-228, 8-229, 8-230, 8-231, 8-232, 8-233, 8-234, 8-235, 8-236, 8-242, 8-243, 8-244, 8-246, 9-15, 9-16, 9-17, 9-19, 9-21, 9-35, 9-37, 9-39, 9-90, 9-92, 9-93, 9-94, 9-95, 9-96, 9-97, 9-98, 9-99, 9-100, 9-101, 9-102, 9-103, 9-104, 9-105, 9-106, 9-107, 9-108, 9-109, 9-110, 9-111, 9-112, 10-11, 10-15, 10-16, 10-17, 10-19, 10-21, 10-35, 10-37, 10-39, 10-90, 10-92, 10-93, 10-94, 10-95, 10-96, 10-97, 10-98, 10-99, 10-100, 10-101, 10-102, 10-103, 10-104, 10-105, 10-106, 10-107, 10-108, 10-109, 10-110, 10-111, 10-112, 11-5, 11-11, 11-12, 11-13, 11-37, 12-5, 12-11, 12-12, 12-13, 12-37, 13-5, 13-11, 13-12, 13-13, 13-37, 14-5, 14-11, 14-12, 14-13, 14-37, 14-42, 14-43, 14-44, 14-45, 14-46, 14-47, 14-48, 14-49, 14-50, 14-51, 14-52, 14-53, 14-54, 14-55, 14-61, 14-62, 14-64, 14-65, 14-66, 14-67, 14-68, 14-69, 14-70, 14-73, 14-74, 14-75, 14-76, 14-77, 14-78, 14-84, 14-85, 14-86, 14-88, 15-5, 15-11, 15-12, 15-13, 15-37, 15-42, 15-43, 15-44, 15-45, 15-46, 15-47, 15-48, 15-49, 15-50, 15-51, 15-52, 15-53, 15-54, 15-55, 15-61, 15-62, 15-64, 15-65, 15-66, 15-67, 15-68, 15-69, 15-70, 15-73, 15-74, 15-75, 15-76, 15-77, 15-78, 15-84, 15-85, 15-86, 15-88, 16-5, 16-11, 16-12, 16-13, 16-37, 17-5, 17-11, 17-12, 17-13, 17-37, 18-2, 18-3, 18-4, 18-5, 18-16, 19-2, 19-3, 19-4, 19-5, 19-16, 20-2, 20-3, 20-4, 20-5, 20-16, 20-30, 20-33, 20-37, 20-39, 20-42, 20-52, 20-53, 20-70, 20-71, 20-79, 20-80, 23-2, 23-3, 23-4, 23-5, 23-16, 24-2, 24-3, 24-4, 24-5, 24-16, 25-2, 25-3, 25-4, 25-5, 25-16, 28-2, 28-3, 28-4, 28-5, 28-16, 28-17, 28-18, 28-19, 28-20, 28-21, 28-22, 28-23, 28-24, 28-25, 28-31, 28-32, 28-33, 28-34, 28-35, 28-36, 28-37, 28-38, 28-39, 28-40, 28-41, 28-42, 28-43, 29-2, 29-3, 29-4, 29-5, 29-16, 29-17, 29-18, 29-19, 29-20, 29-21, 29-22, 29-23, 29-24, 29-25, 29-31, 29-32, 29-33, 29-34, 29-35, 29-36, 29-37, 29-38, 29-39, 29-40, 29-41, 29-42, 29-43, 30-2, 30-3, 30-4, 30-5, 30-16, 30-17, 30-18, 30-19, 30-20, 30-21, 30-22, 30-23, 30-24, 30-25, 30-31, 30-32, 30-33, 30-34, 30-35, 30-36, 30-37, 30-38, 30-39, 30-40, 30-41, 30-42, 30-43, 31-2, 31-3, 31-4, 31-5, 31-16, 31-17, 32-2, 32-3, 32-4, 32-5, 32-16, 32-17, 33-2, 33-3, 33-4, 33-5, 33-16, 33-17, 33-18, 33-19, 33-20, 33-21, 33-22, 33-23, 33-24, 33-25, 33-31, 33-32, 33-33, 33-34, 33-35, 33-36, 33-37, 33-38, 33-39, 33-40, 33-41, 33-42, 33-43, 33-49, 33-50, 33-51, 33-53, 34-2, 34-3, 34-4, 34-5, 34-16, 34-17, 34-18, 34-19, 34-20, 34-21, 34-22, 34-23, 34-24, 34-25, 34-31, 34-32, 34-33, 34-34, 34-35, 34-36, 34-37, 34-38, 34-39, 34-40, 34-41, 34-42, 34-43, 34-49, 34-50, 34-51, 34-53, 35-2, 35-3, 35-4, 35-5, 35-16, 35-17, 35-18, 35-19, 35-20, 35-21, 35-22, 35-23, 35-24, 35-25, 35-31, 35-32, 35-33, 35-34, 35-35, 35-36, 35-37, 35-38, 35-39, 35-40, 35-41, 35-42, 35-43, 35-49, 35-50, 35-51, 35-53, 36-2, 36-3, 36-4, 36-5, 36-16, 36-17, 37-2, 37-3, 37-4, 37-5, 37-16, 37-17, 38-2, 38-3, 38-4, 38-5, 38-31, 38-34, 38-38, 38-40, 38-43, 39-2, 39-3, 39-4, 39-5, 39-31, 39-34, 39-38, 39-40, 39-43, 40-2, 40-3, 40-4, 40-5, 40-31, 40-34, 40-38, 40-40, 40-43, 43-2, 43-3, 43-4, 43-5, 43-31, 43-34, 43-38, 43-40, 43-43, 44-2, 44-3, 44-4, 44-5, 44-31, 44-34, 44-38, 44-40, 44-43, 45-2, 45-3, 45-4, 45-5, 45-31, 45-34, 45-38, 45-40, 45-43, 58-2, 58-3, 58-4, 58-5, 58-16, 58-17, 59-2, 59-3, 59-4, 59-5, 59-16, 59-17, 60-2, 60-3, 60-4, 60-5, 60-16, 60-17, 63-2, 63-3, 63-4, 63-5, 63-16, 63-17, 64-2, 64-3, 64-4, 64-5, 64-16, 64-17, 65-2, 65-3, 65-4, 65-5, 65-16, 65-17, 77-2, 77-3, 77-4, 77-5, 78-2, 78-3, 78-4, 78-5, 78-16, 78-17, 79-2, 79-3, 79-4, 79-5, 79-16, 79-17, 80-2, 80-3, 80-4, 80-5, 80-16, 80-17, 83-2, 83-3, 83-4, 83-5, 83-16, 83-17, 84-2, 84-3, 84-4, 84-5, 84-16, 84-17, 85-2, 85-3, 85-4, 85-5, 85-16, 85-17, 88-1, 88-2, 88-3, 88-4, 88-5, 88-6, 89-1, 89-2, 89-3, 89-4, 89-5, 89-6, 90-1, 90-2, 90-3, 90-4, 90-5, 90-6, 93-1, 93-2, 93-3, 93-4, 93-5, 93-6, 94-1, 94-2, 94-3, 94-4, 94-5, 94-6, 95-1, 95-2, 95-3, 95-4, 95-5, 95-6, 98-1, 98-2, 98-3, 98-4, 98-5, 98-6, 103-1, 103-2, 103-3, 103-4, 103-5, 103-6, 104-1, 104-2, 104-3, 104-4, 104-5, 104-6, 105-1, 105-2, 105-3, 105-4, 105-5, 105-6, 138-2, 138-3, 138-4, 138-5, 138-6, 138-7, 138-8, 138-9, 138-10, 138-11, 138-12, 138-13, 138-14, 138-15, 138-16, 138-17, 138-18, 138-19, 138-20, 138-21, 138-22, 138-23, 138-24, 138-25, 138-26, 138-27, 138-28, 138-29, 138-30, 138-31, 138-32, 138-33, 138-34, 138-35, 138-36, 138-37, 138-38, 138-39, 138-40, 138-41, 138-42, 138-43, 138-44, 138-45, 138-46, 138-47, 138-48, 138-49, 138-50, 138-51, 138-52, 138-53, 138-54, 138-55, 138-56, 138-57, 138-58, 138-59, 138-60, 138-61, 138-62, 138-63, 138-64, 138-65, 138-66, 138-67, 138-68, 138-69, 138-70, 138-71, 138-72, 138-73, 138-74, 138-75, 138-76, 138-77, 138-78, 138-79, 138-80, 138-81, 138-82, 138-83, 138-84, 138-85, 138-86, 138-87, 138-88, 138-89, 138-90, 138-91, 138-92, 138-93, 138-94, 138-95, 138-96, 138-97, 138-98, 138-99, 138-104, 138-105, 138-106, 138-107, 138-108, 138-111, 138-112, 138-113, 138-114, 138-115, 138-120, 138-121, 138-122, 138-123, 138-124, 138-127, 138-128, 138-129, 138-130, 138-131, 138-136, 138-137, 138-138, 138-139, 138-140, 138-143, 138-144, 138-145, 138-146, 138-147, 138-152, 138-153, 138-154, 138-155, 138-156, 138-159, 138-160, 138-161, 138-162, 138-163, 138-168, 138-169, 138-170, 138-171, 138-172, 138-175, 138-176, 138-177, 138-178, 138-179, 138-184, 138-185, 138-186, 138-187, 138-188, 138-191, 138-192, 138-193, 138-194, 138-195, 138-200, 138-201, 138-202, 138-203, 138-204, 138-207, 138-208, 138-209, 138-210, 138-211, 138-216, 138-217, 138-218, 138-219, 138-220, 138-223, 138-224, 138-225, 138-226, 138-227, 138-232, 138-233, 138-234, 138-235, 138-236, 138-239, 138-240, 138-241, 138-242, 138-243, 138-248, 138-249, 138-250, 138-251, 138-252, 138-255, 138-256, 138-257, 138-258, 138-259, 138-264, 138-265, 138-266, 138-267, 138-268, 138-271, 138-272, 138-273, 138-274, 138-275, 138-285, 138-295, 138-305, 138-315, 138-325, 139-24, 139-31, 140-2, 140-31, 141-23, 141-30, 142-23, 142-30, 143-23, 143-30, 144-8, 144-13, 144-18, 144-28, 144-33, 144-63, 145-1, 145-6, 145-7, 145-8, 145-9, 145-10, 145-13, 145-14, 145-15, 145-16, 145-17, 145-22, 145-23, 145-24, 145-25, 145-26, 145-29, 145-30, 145-31, 145-32, 145-33, 145-38, 145-39, 145-40, 145-41, 145-42, 145-45, 145-46, 145-47, 145-48, 145-49, 145-54, 145-55, 145-56, 145-57, 145-58, 145-61, 145-62, 145-63, 145-64, 145-65, 145-70, 145-71, 145-72, 145-73, 145-74, 145-77, 145-78, 145-79, 145-80, 145-81, 145-86, 145-87, 145-88, 145-89, 145-90, 145-93, 145-94, 145-95, 145-96, 145-97, 145-102, 145-111, 145-112, 145-118, 145-127, 145-128, 145-134, 145-143, 145-144, 145-150, 145-159, 145-160, 145-166, 145-175, 145-176, 145-182, 145-191, 145-192, 145-198, 145-207, 145-208, 145-214, 145-223, 145-224, 145-230, 145-239, 145-240, 145-246, 145-255, 145-256, 145-262, 145-271, 145-272, 145-273, 145-283, 145-293, 145-303, and 145-313;
(2) the following compounds are more preferred: compounds Nos. 1-15, 1-35, 1-37, 1-39, 1-95, 1-110, 1-179, 1-189, 1-190, 1-191, 1-204, 1-205, 1-206, 1-207, 1-208, 1-209, 1-210, 1-212, 1-213, 1-219, 1-222, 1-223, 1-224, 1-225, 1-226, 1-227, 1-228, 1-229, 1-230, 1-231, 1-232, 1-233, 1-234, 1-235, 1-236, 1-242, 1-243, 1-244, 3-15, 3-35, 3-37, 3-39, 3-95, 3-110, 3-179, 3-189, 3-190, 3-191, 3-204, 3-205, 3-206, 3-207, 3-208, 3-209, 3-210, 3-212, 3-213, 3-219, 3-222, 3-223, 3-224, 3-225, 3-226, 3-227, 3-228, 3-229, 3-230, 3-231, 3-232, 3-233, 3-234, 3-235, 3-236, 3-242, 3-243, 3-244, 4-15, 4-35, 4-37, 4-39, 4-95, 4-96, 4-98, 4-106,4-110, 4-143, 4-150, 4-179, 4-189, 4-190, 4-191, 4-193, 4-204, 4-205, 4-206, 4-207, 4-208, 4-209, 4-210, 4-211, 4-212, 4-213, 4-214, 4-215, 4-216, 4-217, 4-218, 4-219, 4-220, 4-221, 4-222, 4-223, 4-224, 4-225, 4-226, 4-227, 4-228, 4-229, 4-230, 4-231, 4-232, 4-233, 4-234, 4-235, 4-236, 4-242, 4-243, 4-244, 5-15, 5-35, 5-37, 5-39, 5-95, 5-110, 6-15, 6-35, 6-37, 6-39, 6-95, 6-96, 6-110, 6-179, 6-189, 6-190, 6-191, 6-204, 6-205, 6-206, 6-207, 6-208, 6-209, 6-210, 6-212, 6-213, 6-219, 6-222, 6-223, 6-224, 6-225, 6-226, 6-227, 6-228, 6-229, 6-230, 6-231, 6-232, 6-233, 6-234, 6-235, 6-236, 6-242, 6-243, 6-244, 7-15, 7-35, 7-37, 7-39, 7-95, 7-110, 7-179, 7-189, 7-190, 7-191, 7-204, 7-205, 7-206, 7-207, 7-208, 7-209, 7-210, 7-212, 7-213, 7-219, 7-222, 7-223, 7-224, 7-225, 7-226, 7-227, 7-228, 7-229, 7-230, 7-231, 7-232, 7-233, 7-234, 7-235, 7-236, 7-242, 7-243, 7-244, 8-15, 8-35, 8-37, 8-39, 8-95, 8-110, 8-179, 8-189, 8-190, 8-191, 8-204, 8-205, 8-206, 8-207, 8-208, 8-209, 8-210, 8-212, 8-213, 8-219, 8-222, 8-223, 8-224, 8-225, 8-226, 8-227, 8-228, 8-229, 8-230, 8-231, 8-232, 8-233, 8-234, 8-235, 8-236, 8-242, 8-243, 8-244, 9-15, 9-35, 9-37, 9-39, 9-95, 9-110, 14-5, 14-11, 14-12, 14-13, 14-37, 14-44, 14-45, 14-47, 14-64, 14-67, 14-73, 14-75, 14-78, 14-84, 14-85, 14-86, 15-5, 15-11, 15-12, 15-13, 15-37, 15-44, 15-45, 15-47, 15-64, 15-67, 15-73, 15-75, 15-78, 15-84, 15-85, 15-86, 17-11, 20-53, 20-71, 20-80, 28-2, 28-3, 28-4, 28-5, 28-16, 28-17, 28-19, 28-22, 28-31, 28-34, 28-38, 28-40, 28-43, 30-3, 33-2, 33-3, 33-4, 33-5, 33-16, 33-17, 33-19, 33-22, 33-31, 33-34, 33-38, 33-40, 33-43, 33-49, 33-50, 33-51, 34-2, 34-3, 34-4, 34-5, 34-16, 34-17, 34-19, 34-22, 34-31, 34-34, 34-38, 34-40, 34-43, 35-49, 35-50, 35-51, 35-2, 35-3, 35-4, 35-5, 35-16, 35-17, 35-19, 35-22, 35-31, 35-34, 35-38, 35-40, 35-43, 35-49, 35-50, 35-51, 37-3, 38-2, 38-3, 38-4, 38-5, 39-2, 39-3, 39-4, 39-5, 40-2, 40-3, 40-4, 40-5, 43-2, 43-3, 43-4, 43-5, 44-2, 44-3, 44-4, 44-5, 45-2, 45-3, 45-4, 45-5, 77-3, 138-2, 138-3, 138-8, 138-9, 138-10, 138-11, 138-12, 138-15, 138-16, 138-17, 138-18, 138-19, 138-24, 138-25, 138-26, 138-27, 138-28, 138-31, 138-32, 138-33, 138-34, 138-35, 138-40, 138-41, 138-42, 138-43, 138-44, 138-47, 138-48, 138-49, 138-50, 138-51, 138-56, 138-57, 138-58, 138-59, 138-60, 138-63, 138-64, 138-65, 138-66, 138-67, 138-72, 138-73, 138-74, 138-75, 138-76, 138-79, 138-80, 138-81, 138-82, 138-83, 138-88, 138-89, 138-90, 138-91, 138-92, 138-95, 138-96, 138-97, 138-98, 138-104, 138-120, 138-136, 138-152, 138-168, 138-184, 138-200, 138-216, 138-232, 138-248, 138-264, 138-275, 138-285, 138-295, 138-305, 138-315, 138-325, 139-24, 139-31, 140-2, 140-31, 141-23, 141-30, 142-23, 142-30, 143-23, 143-30, 144-13, 144-63, 145-6, 145-15, 145-16, 145-22, 145-31, 145-32, 145-47, 145-48, 145-54, 145-63, 145-64, 145-70, 145-79, 145-80, 145-86, 145-95, 145-96, 145-102, 145-118, 145-134, 145-150, 145-166, 145-182, 145-198, 145-214, 145-230, 145-246, 145-262, 145-273, 145-283, 145-293, 145-303 and 145-313;
(3) Much more preferred compounds are selected from the group of the following compounds:
1) 2-ethoxy-3-[4-[2-(4-pyridyl-2-ylbenzoylamino)ethoxy]phenyl]propionic acid
2) 3-[4-[2-(4-pyridyl-2-ylbenzoylamino)ethoxy]phenyl]-2-propylpropionic acid
3) 2-butyl-3-[4-[2-(4-pyridyl-2-ylbenzoylamino)ethoxy]phenyl]propionic acid
4) 3-[4-[2-(biphenyl-4-carbonylamino)ethoxy]phenyl]-2-butylpropionic acid
5) 2-butyl-3-[4-[2-(4xe2x80x2-formylbiphenyl-4-carbonylamino)ethoxy]phenyl]propionic acid
6) 2-butyl-3-[4-[2-(4xe2x80x2-dimethylaminomethylbiphenyl-4-carbonylamino)ethoxy]-phenyl]propionic acid
7) 2-butyl-3-[4-[2-(4xe2x80x2-carboxybiphenyl-4-carbonylamino)ethoxy]phenyl]propionic acid
8) 2-butyl-3-[4-[2-(3xe2x80x2-methoxybiphenyl-4-carbonylamino)ethoxy]phenyl]propionic acid
9) 2-butyl-3-[4-[2-(3xe2x80x2-hydroxybiphenyl-4-carbonylamino)ethoxy]phenyl]propionic acid
10) 2-butyl-3-[4-[2-(2xe2x80x2-methoxybiphenyl-4-carbonylamino)ethoxy]phenyl]propionic acid
11) 2-butyl-3-[4-[2-(4xe2x80x2-hydroxy-3,5-dimethylbiphenyl-4-carbonylamino)ethoxy]-phenyl]propionic acid
12) 2-butyl-3-[4-[2-(2-methoxypyridine-5-carbonylamino)ethoxy]phenyl]propionic acid
13) 2-butyl-3-[4-[2-(4-diethylaminobenzoylamino)ethoxy]phenyl]propionic acid
14) 2-butyl-3-[4-[3-(4-pyridyl-2-ylbenzoylamino)propoxy]phenyl]propionic acid
15) 2-phenoxy-3-[4-[2-(4-pyridyl-2-ylbenzoylamino)ethoxy]phenyl]propionic acid
16) 3-[4-[2-(biphenyl-4-carbonylamino)ethoxy]phenyl]-2-phenoxypropionic acid
17) 3-[4-[2-(4xe2x80x2-fluorobiphenyl-4-carbonylamino)ethoxy]phenyl]-2-phenoxypropionic acid
18) 3-[4-[2-(4xe2x80x2-chlorobiphenyl-4-carbonylamino)ethoxy]phenyl]-2-phenoxypropionic acid
19) 3-[4-[2-(4xe2x80x2-trifluoromethylbiphenyl-4-carbonylamino)ethoxy]phenyl]-2-phenoxypropionic acid
20) 2-(4-isopropylphenoxy)-3-[4-[2-(4-pyridyl-2-ylbenzoylamino)-ethoxy]phenyl]propionic acid
21) 3-[4-[2-(biphenyl-4-carbonylamino)ethoxy]phenyl]-2-(4-isopropylphenoxy)-propionic acid
22) 2-(4-isopropylphenoxy)-3-[4-[2-(2-phenylpyridine-5-carbonylamino)-ethoxy]phenyl]propionic acid
23) 2-(4-isopropylphenoxy)-3-[4-[2-[2-(4-methoxyphenyl)pyridine-5-carbonylamino)ethoxy]phenyl]propionic acid
24) 3-[4-[2-[2-(4-fluorophenyl)pyridine-5-carbonylamino]ethoxy]phenyl]-2-(4-isopropylphenoxy)propionic acid
25) 3-[4-[2-[2-(2,2,3,3-tetrafluoropropoxy)pyridine-5-carbonylamino]ethoxy]phenyl]-2-(4-isopropylphenoxy)propionic acid
26) 2-(4-isopropylphenoxy)-3-[4-[2-[4-(3-trifluoromethylpyridine-6-yl)benzoylamino]ethoxy]phenyl]propionic acid
27) 2-(4-isopropylphenoxy)-3-[4-[2-[4-(3-nitropyridine-6-yl)-benzoylamino]ethoxy]phenyl]propionic acid
28) 2-(4-isopropylphenoxy)-3-[4-[2-[4-(3-methoxypyridine-6-yl)-benzoylamino]ethoxy]phenyl]propionic acid
29) 2-(4-isopropylphenoxy)-3-[4-[2-[4-(3-dimethylaminopyridine-6-yl)benzoylamino]ethoxy]phenyl]propionic acid
30) 2-(4-methoxyphenoxy)-3-[4-[2-(4-pyridyl-2-ylbenzoylamino)ethoxy]-phenyl]propionic acid
31) 2-(3-phenylpropyl)-3-[4-[2-(4-pyridyl-2-ylbenzoylamino)ethoxy]phenyl]propionic acid
32) 2-(4-methylphenoxy)-3-[4-[2-(4-pyridyl-2-ylbenzoylamino)ethoxy]-phenyl]propionic acid
33) 2-(4-t-butylphenoxy)-3-[4-[2-(4-pyridyl-2-ylbenzoylamino)ethoxy]phenyl]-propionic acid
34) 2-(4-fluorophenoxy)-3-[4-[2-(4-pyridyl-2-ylbenzoylamino)ethoxy]phenyl]propionic acid
35) 2-(4-chlorophenoxy)-3-[4-[2-(4-pyridyl-2-ylbenzoylamino)ethoxy]phenyl]propionic acid 36) 2-(4-trifluoromethylphenoxy)-3-[4-[2-(4-pyridyl-2-ylbenzoylamino)ethoxy]phenyl]-propionic acid
37) 2-(4-trifluoromethoxyphenoxy)-3-[4-[2-(4-pyridyl-2-ylbenzoylamino)ethoxy]-phenyl]propionic acid
38) 2-(3-fluorophenoxy)-3-[4-[2-(4-pyridyl-2-ylbenzoylamino)ethoxy]phenyl]propionic acid
39) 2-(3,5-difluorophenoxy)-3-[4-[2-(4-pyridyl-2-ylbenzoylamino)ethoxy]phenyl]-propionic acid
40) 2-(3,4-difluorophenoxy)-3-[4-[2-(4-pyridyl-2-ylbenzoylamino)ethoxy]phenyl]-propionic acid
41) 2-(3,4,5-trifluorophenoxy)-3-[4-[2-(4-pyridyl-2-ylbenzoylamino)ethoxy]phenyl]-propionic acid
42) 2-(2,3,4,5,6-pentafluorophenoxy)-3-[4-[2-(4-pyridyl-2-ylbenzoylamino)ethoxy]-phenyl]propionic acid
43) 2-methyl-2-phenoxy-3-[4-[2-(4-pyridyl-2-ylbenzoylamino)ethoxy]phenyl]-propionic acid
44) 2-(4-isopropylphenoxy)-2-methyl-3-[4-[2-(4-pyridyl-2-ylbenzoylamnino)ethoxy]-phenyl]propionic acid
45) 2-(4-isopropylphenoxy)-3-[4-[2-[2-(4-methoxyphenyl)pyridine-5-carbonylamino]-ethoxy]phenyl]-2-methylpropionic acid and
46) 3-[4-[2-[2-(2,2,3,3-tetrafluoropropoxy)pyridine-5-carbonylamino]ethoxy]phenyl]-2-(4-isopropylphenoxy)-2-methylpropionic acid
and pharmaceutically acceptable salts and esters thereof.
(4) Most preferred compounds are selected from the group of the following compounds:
1) 2-ethoxy-3-[4-[2-(4-pyridyl-2-ylbenzoylamino)ethoxy]phenyl]propionic acid
2) 3-[4-[2-(4-pyridyl-2-ylbenzoylamino)ethoxy]phenyl]-2-propylpropionic acid
3) 2-butyl-3-[4-[2-(4-pyridyl-2-ylbenzoylamino)ethoxy]phenyl]propionic acid
4) 2-butyl-3-[4-[2-(4xe2x80x2-formylbiphenyl-4-carbonylamino)ethoxy]phenyl]propionic acid
5) 2-butyl-3-[4-[2-(4xe2x80x2-hydroxy-3,5-dimethybiphenyl-4-carbonylamino)ethoxy]-phenyl]propionic acid
6) 2-phenoxy-3-[4-[2-(4-pyridyl-2-ylbenzoylamino)ethoxy]phenyl]propionic acid
7) 3-[4-[2-(biphenyl-4-carbonylamino)ethoxy]phenyl]-2-phenoxypropionic acid
8) 3-[4-[2-(4xe2x80x2-fluorobiphenyl-4-carbonylamino)ethoxy]phenyl]-2-phenoxypropionic acid
9) 3-[4-[2-(4xe2x80x2-chlorobiphenyl-4-carbonylamino)ethoxy]phenyl]-2-phenoxypropionic acid
10) 2-(4-isopropylphenoxy)-3-[4-[2-(4-pyridyl-2-ylbenzoylamino)ethoxy]phenyl]propionic acid
11) 3-[4-[2-(biphenyl-4-carbonylamino)ethoxy]phenyl]-2-(4-isopropylphenoxy)-propionic acid
12) 2-(4-isopropylphenoxy)-3-[4-[2-(2-phenylpyridine-5-carbonylamino)ethoxy]phenyl]propionic acid
13) 2-(4-isopropylphenoxy)-3-[4-[2-[2-(4-methoxyphenyl)pyridine-5-carbonylamino]ethoxy]phenyl]propionic acid
14) 3-[4-[2-[2-(4-fluorophenyl)pyridine-5-carbonylamino]ethoxy]phenyl]-2-(4-isopropylphenoxy)propionic acid
15) 3-[4-[2-[2-(2,2,3,3-tetrafluoropropoxy)pyridine-5-carbonylamino]ethoxy]phenyl]-2-(4-isopropylphenoxy)propionic acid
16) 2-(4-isopropylphenoxy)-3-[4-[2-[4-(3-methoxypyridine-6-yl)-benzoylamino]ethoxy]phenyl]propionic acid
17) 2-(4-isopropylphenoxy)-3-[4-[2-[4-(3-dimethylaminopyridine-6-yl)benzoylamino]ethoxy]phenyl]propionic acid
18) 2-(4-methoxyphenoxy)-3-[4-[2-(4-pyridyl-2-ylbenzoylamino)ethoxy]phenyl]propionic acid
19) 2-(4-methylphenoxy)-3-[4-[2-(4-pyridyl-2-ylbenzoylamino)ethoxy]phenyl]propionic acid
20) 2-(4-t-butylphenoxy)-3-[4-[2-(4-pyridyl-2-ylbenzoylamino)ethoxy]phenyl]propionic acid
21) 2-(4-fluorophenoxy)-3-[4-[2-(4-pyridyl-2-ylbenzoylamino)ethoxy]phenyl]propionic acid
22) 2-(4-chlorophenoxy)-3-[4-[2-(4-pyridyl-2-ylbenzoylamino)ethoxy]phenyl]propionic acid
23) 2-(4-trifluoromethylphenoxy)-3-[4-[2-(4-pyridyl-2-ylbenzoylamino)ethoxy]phenyl]propionic acid
24) 2-(4-trifluoromethoxyphenoxy)-3-[4-[2-(4-pyridyl-2-ylbenzoylamino)ethoxy]phenyl]propionic acid
25) 2-(3-fluorophenoxy)-3-[4-[2-(4-pyridyl-2-ylbenzoylamino)ethoxy]phenyl]propionic acid
26) 2-(3,4,5-trifluorophenoxy)-3-[4-[2-(4-pyridyl-2-ylbenzoylamino)ethoxy]phenyl]propionic acid
27) 2-methyl-2-phenoxy-3-[4-[2-(4-pyridyl-2-ylbenzoylamino)ethoxy]phenyl]propionic acid
28) 2-(4-isopropylphenoxy)-2-methyl-3-[4-[2-(4-pyridyl-2-yl-benzoylamino)ethoxy]phenyl]propionic acid
29) 2-(4-isopropylphenoxy)-3-[4-[2-[2-(4-methoxyphenyl)pyridine-5-carbonylamino]ethoxy]phenyl]-2-methylpropionic acid and
30) 3-[4-[2-[2-(2,2,3,3-tetrafluoropropoxy)pyridine-5-carbonylamino]ethoxy]phenyl]-2(4-isopropylphenoxy)-2-methylpropionic acid
and pharmaceutically acceptable salts and esters thereof.
In the nomenclature herein, reference to a xe2x80x9c(4-pyridyl-2-ylbenzoylamino)xe2x80x9d group should have correctly named the xe2x80x9c(4-pyridine-2-ylbenzoylamino)xe2x80x9d group.
The amidocarboxylic acid derivatives of formula (I) of the present invention, pharmacologically acceptable salts thereof or pharmacologically acceptable esters thereof are easily prepared according to the following method A: 
wherein R1, R2, R3, R4, W, X, Y and Z have the same meanings as defined above; W1 represents an amino group protected by a conventional protecting group such as t-butoxycarbonyl in the case where W represents a primary or secondary amino group and W1 has the same meaning as defined for W in the case where W1 represents other groups; and in the case where the amidocarboxylic acid of formula (I) forms an ester, M represents the ester residue.
Step A1
Step A1 is to prepare a compound of formula (III) and the compound is prepared by acylating a compound of formula (II).
The present reaction is a reaction for forming an amide bond well known in organic synthetic chemistry and is preferably usually carried out in the presence of a solvent.
The solvent employed here is not particularly limited so long as it has no adverse effect on the reaction and includes, for example, an inert solvent, preferably halogenated hydrocarbons such as dichloromethane and chloroform; esters such as ethyl acetate; ethers such as tetrahydrofuran and dioxane; and amides such as N,N-dimethylacetamide and N,N-dimethylformamide.
The reaction is carried out by treatment with a condensation agent.
The condensation agent employed here includes carbodiimides such as N,N-dicyclohexylcarbodiimide and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; phosphoryl compounds such as diphenylphosphoryl azide and diethylphosphoryl cyanide; carbonyldiimidazole; and triphenylphosphine-diethyl azodicarbonate; preferably carbonyldiimidazole and carbodiimides. In the case where phosphoryl compounds are employed, the reaction is preferably carried out in the presence of a tertiary amine such as triethylamine and N-methylmorpholine.
Alternatively, the present reaction is accomplished by reacting the carboxylic acid used in the present reaction or a salt thereof with a lower alkyl ester of chloroformic acid such as ethyl chloroformate and isobutyl chloroformate in the presence of a tertiary amine such as triethylamine and N-methylmorpholine to form a mixed acid anhydride or by reacting the carboxylic acid used in the present reaction or a salt thereof with N-hydroxysuccinimide, N-hydroxybenzotriazole or p-nitrophenol in the presence of carbodiimides such as N,N-dicyclohexylcarbodiimide to form the corresponding activated ester, and thereafter, by condensing these compounds with amines.
The reaction is preferably usually carried out in the presence of a solvent. The solvent employed here is not particularly limited so long as it has no adverse effect on the reaction and includes, for example, an inert solvent, preferably halogenated hydrocarbons such as dichloromethane and chloroform; ethers such as tetrahydrofuran and dioxane; and aromatic hydrocarbons such as benzene and toluene.
As a further alternative, the compound is obtained by reacting the carboxylic acid used in the present reaction or a salt thereof with a halogenating agent, preferably phosphorus pentachloride, oxalyl chloride or thionyl chloride to afford the corresponding acyl halide and then by reacting the acyl halide with amines in a similar manner to that described above.
The reaction is preferably usually carried out in the presence of a solvent. The solvent employed here is not particularly limited so long as it has no adverse effect on the present reaction and includes, for example, an inert solvent, preferably halogenated hydrocarbons such as dichloromethane; ethers such as tetrahydrofuran and dioxane; and aromatic hydrocarbons such as benzene and toluene.
The reaction is carried out at xe2x88x9220xc2x0 C. to 100xc2x0 C., preferably at xe2x88x925xc2x0 C. to 50xc2x0 C.
While the reaction time varies depending on the reagent, the reaction temperature and the solvent, it is usually 30 minutes to 24 hours, preferably 1 hour to 16 hours.
Step A2
Step A2 is to prepare a phenylalkylcarboxylic acid derivative of formula (I) and is carried out by removal of an ester residue from the compound of formula (III).
The present step is accomplished by hydrolysis with a base in the presence of a solvent.
In the present reaction, the solvent employed here is not particularly limited so long as it has no adverse effect on the reaction and preferably includes, for example, ethers such as diethyl ether, tetrahydrofuran and dioxane; alcohols such as methanol, ethanol and methoxyethanol; water; or a mixture of these solvents.
The base employed in the reaction includes, for example, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; and alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate; preferably the alkali metal hydroxides.
The reaction temperature varies depending on the solvent and the base used but is 0xc2x0 C. to 140xc2x0 C., preferably 10xc2x0 C. to 120xc2x0 C.
While the reaction time varies depending on the solvent, the base and the reaction temperature employed, it is usually 10 minutes to 24 hours, preferably 30 minutes to 16 hours.
Alternatively, in the case where the ester residue is a t-butyl group, a diphenylmethyl group or a p-methoxybenzyl group, the present step is carried out by reacting the ester with an organic acid such as formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and trifluoromethanesulfonic acid or a mineral acid such as hydrochloric acid and sulfuric acid, preferably trifluoroacetic acid or hydrochloric acid in the presence or absence of a solvent.
In the case where a solvent is used in the present reaction, the solvent is not particularly limited so long as it has no adverse effect on the reaction and includes, for example, hydrocarbons such as benzene, toluene, xylene, hexane and heptane; halogenated hydrocarbons such as chloroform, methylene chloride and carbon tetrachloride; ethers such as diethyl ether, tetrahydrofuran and dioxane; alcohols such as methanol and ethanol; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and hexamethylphosphoric triamide; esters such as methyl acetate and ethyl acetate; water; or a mixture of these solvents; preferably ethers.
While the reaction temperature varies depending on the acid used, it is xe2x88x9210xc2x0 C. to 120xc2x0 C., preferably 0xc2x0 C. to 100xc2x0 C.
While the reaction time varies depending on the acid used and the reaction temperature, it is usually 10 minutes to 24 hours, preferably 30 minutes to 16 hours.
As a further alternative, the present step is accomplished by carrying out a catalytic hydrogenation reaction on the compound of the formula (III) in the case where the ester residue is an aralkyl group such as a benzyl group or a diphenylmethyl group. The catalyst employed here includes, for example, palladium on carbon, palladium black, platinum oxide and platinum black, preferably palladium on carbon.
The reaction is preferably usually carried out in the presence of a solvent. The solvent employed here is not particularly limited so long as it has no adverse effect on the reaction and includes, for example, hydrocarbons such as benzene, toluene, xylene, hexane and heptane; halogenated hydrocarbons such as chloroform, methylene chloride and carbon tetrachloride; ethers such as diethyl ether, tetrahydrofuran and dioxane; alcohols such as methanol, ethanol and isopropanol; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and hexamethylphosphoric triamide; carboxylic acids such as formic acid and acetic acid; or a mixture of these solvents; preferably alcohols.
The reaction temperature is 10xc2x0 C. to 140xc2x0 C., preferably 20xc2x0 C. to 120xc2x0 C.
The reaction time varies depending on the reagent, the reaction temperature and the solvent and is usually 30 minutes to 3 days, preferably 1 hour to 24 hours.
As another alternative, in the case where W1 represents a primary or secondary amino group protected by a conventional protecting group such as a t-butoxycarbonyl, after the above reaction, deprotection can be carried out according to a known method, for example, by reacting the protected amino compound with an acid such as hydrochloric acid at room temperature for 30 minutes to 2 hours.
In the formula (II) of Method A, the compound (IIa) in which R1 has the hydrogen atom can be also prepared according to Method B or Method C. 
wherein
R2, R3, R4, Y, Z, W1 and M have the same meanings as defined above.
P represents a conventional protecting group for a hydroxyl group such as a 2-tetrahydropyranyl group or a methoxymethyl group; U represents a hydroxyl group, a halogen atom (preferably a chlorine atom, a bromine atom or an iodine atom) or a group of the formula: xe2x80x94Oxe2x80x94SO2xe2x80x94R6 (wherein R6 represents an alkyl group having from 1 to 6 carbon atoms such as a methyl or ethyl group; a halogenated alkyl group having from 1 to 4 carbon atoms such as a trifluoromethyl group; or an aryl group having from 6 to 10 carbon atoms which may have an alkyl group having from 1 to 4 carbon atoms, a nitro group or halogen atom as a substituent, such as a phenyl, p-tolyl, p-nitrophenyl or p-bromophenyl group). U1 represents a halogen atom or a group of formula: xe2x80x94Oxe2x80x94SO2xe2x80x94R6 (wherein R6 has the same meaning as defined above for U).
Step B1
Step B1 in Method B is to prepare a compound of formula (VI) and the compound is prepared by reacting a compound of formula (IV) with a compound of formula (V).
In the case where U is a hydroxyl group, the reaction is carried out according to the conventional Mitsunobu reaction [O. Mitsunobu, Synthesis, page 1, (1981)].
The reaction is usually carried out by contacting azo compounds with phosphines in the presence of a solvent. As the azo compound of the reagent, C1-C4 alkyl azodicarboxylates such as diethyl azodicarboxylate and azodicarboxamides such as 1,1xe2x80x2-(azodicarbonyl)dipiperidine are used. As the phosphines, triarylphosphines such as triphenylphosphine and tri (C1-C4 alkyl)phosphines such as tributylphosphine are used.
The reaction is preferably usually carried out in the presence of a solvent. The solvent employed here is not particularly limited so long as it has no adverse effect on the present reaction and includes, for example, hydrocarbons such as benzene, toluene, xylene, hexane and heptane; halogenated hydrocarbons such as chloroform, methylene chloride, carbon tetrachloride and 1,2-dichloroethane; ethers such as diethyl ether, tetrahydrofuran and dioxane; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and hexamethylphosphoric triamide; or a mixture of these solvents; preferably the hydrocarbons, halogenated hydrocarbons or ethers. The reaction temperature is 10xc2x0 C. to 100xc2x0 C., preferably 20xc2x0 C. to 80xc2x0 C.
While the reaction time varies depending on the reagent, the reaction temperature and the solvent, it is usually 1 hour to 3 days, preferably 5 hours to 2 days.
In the case where U represents a halogen atom or a group of formula: xe2x80x94Oxe2x80x94SO2xe2x80x94R6 (wherein R6 has the same meaning as defined above), the reaction is carried out in an inert solvent in the presence of a base.
The base employed here preferably includes alkali metal carbonates such as sodium carbonate and potassium carbonate; alkali metal hydrides such as sodium hydride, potassium hydride and lithium hydride; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide and lithium methoxide; alkyl lithiums such as butyl lithium and methyl lithium; lithium amides such as lithium diethylamide, lithium diisopropylamide and lithium bis(trimethylsilyl)amide; alkali metal hydrogencarbonates such as sodium hydrogencarbonate and potassium hydrogencarbonate; and tertiary organic amines such as 1,5-diazabicyclo[4.3.0]non-5-ene, 1,8-diazabicyclo[5.4.0]undec-7-ene and N,N-diisopropylethylamine; more preferably alkali metal carbonates, alkali metal hydrides or alkali metal alkoxides.
The inert solvent used in the reaction is not particularly limited so long as it has no adverse effect on the reaction and includes hydrocarbons such as benzene and toluene; ethers such as tetrahydrofuran and dioxane; alcohols such as methanol, ethanol and t-butanol; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidinone; ketones such as acetone and 2-butanone; nitrites such as acetonitrile; sulfoxides such as dimethyl sulfoxide; or mixtures thereof; preferably ethers, amides, ketones or sulfoxides.
In the case where the present reaction is carried out in the presence of a phase transfer catalyst such as benzyltriethylammonium iodide and tetrabutylammonium iodide, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide are used as the base and the reaction is carried out in a solvent which is a two-layer system of water and a halogenated hydrocarbon such as methylene chloride and chloroform.
The reaction temperature is xe2x88x9210xc2x0 C. to 120xc2x0 C., preferably 10xc2x0 C. to 100xc2x0 C.
While the reaction time varies depending on the reagent used and the reaction temperature, it is usually 30 minutes to 48 hours, preferably 1 hour to 16 hours.
Step B2
Step B2 is to prepare a compound of formula (VII) and is carried out by removal of the hydroxy protecting group such as a 2-tetrahydropyranyl group from the compound of the formula (VI).
The present reaction is carried out in a similar manner to the method of deprotection using an acid described in Step A2 of Method A.
Step B3
Step B3 is to prepare a compound of formula (VIII) and is carried out by converting the hydroxyl group of the compound of formula (VII) to a halogen atom or a group of formula: xe2x80x94Oxe2x80x94SO2xe2x80x94R6 (wherein R6 has the same meaning as defined above).
The halogenation is carried out by reaction of compound (VII) with a hydrohalogenic acid such as hydrochloric acid and hydrobromic acid; halides of inorganic acids such as thionyl chloride, thionyl bromide, phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride and phosphorus oxychloride; Vilsmeier reagents such as N,N-dimethylchloroforminium and N,N-dimethylbromoforminium; or halogenation reagents containing a phosphorus compound such as triphenylphosphine and carbon tetrachloride or carbon tetrabromide, and triethylphosphine dichloride and triethylphosphine dibromide in an inert solvent or without a solvent.
The solvent employed here is not particularly limited so long as it has no adverse effect on the reaction and includes, for example, hydrocarbons such as benzene, toluene, xylene, hexane and heptane; halogenated hydrocarbons such as chloroform, methylene chloride, carbon tetrachloride and 1,2-dichloroethane; ethers such as diethyl ether, tetrahydrofuran and dioxane; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and hexamethylphosphoric triamide; and mixtures thereof; preferably hydrocarbons, halogenated hydrocarbons or ethers.
The reaction temperature is xe2x88x9250xc2x0 C. to 150xc2x0 C., preferably 0xc2x0 C. to 80xc2x0 C.
While the reaction time varies depending on the reagent, the reaction temperature and the solvent, it is usually 30 minutes to 3 days, preferably 1 hour to 24 hours.
The sulfonation reaction is carried out by reaction of compound (VII) with a reagent of formula: R6xe2x80x94SO2xe2x80x94U2 or (R6xe2x80x94SO2)2 (wherein R6 has the same meaning as defined above and U2 represents a halogen atom (preferably a chlorine atom)) in an inert solvent in the presence of a base.
The solvent employed here is not particularly limited so long as it has no adverse effect on the present reaction and includes, for example, hydrocarbons such as benzene, toluene, xylene, hexane and heptane; halogenated hydrocarbons such as chloroform, methylene chloride, carbon tetrachloride and 1,2-dichloroethane; ethers such as diethyl ether, tetrahydrofuran and dioxane; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and hexamethylphosphoric triamide; nitrogen-containing aromatic compounds such as pyridine and collidine; or mixtures thereof; preferably halogenated hydrocarbons or nitrogen-containing aromatic compounds.
The base employed here includes alkali metal carbonates such as sodium carbonate and potassium carbaonate; alkali metal hydrogencarbonates such as sodium hydrogencarbonate and potassium hydrogencarbonate; or tertiary organic amines such as triethylamine, N-methylmorpholine, N,N-diisopropylethylamine, 1,5-diazabicyclo[4.3.0]non-5-ene and 1,8-diazabicyclo[5.4.0]undec-7-ene; preferably tertiary organic amines.
The reaction temperature is xe2x88x9270xc2x0 C. to 100xc2x0 C., preferably 0xc2x0 C. to 80xc2x0 C.
While the reaction time varies depending on the reagent, the reaction temperature and the solvent, it is usually 30 minutes to 48 hours, preferably 1 hour to 16 hours.
Step B4
Step B4 is to prepare a compound of formula (IX) and is carried out by converting the halogen atom or group of formula: xe2x80x94Oxe2x80x94SO2xe2x80x94R6 (wherein R6 has the same meaning as defined above) of the compound of formula (VIII) to an azide group.
The present reaction is carried out by reacting a metal azide such as sodium azide or an organic azide such as tetrabutylammonium azide in an inert solvent.
The solvent employed here is not particularly limited so long as it has no adverse effect on the present reaction and includes, for example, hydrocarbons such as benzene, toluene, xylene, hexane and heptane; halogenated hydrocarbons such as chloroform, methylene chloride, carbon tetrachloride and 1,2-dichloroethane; ethers such as diethyl ether, tetrahydrofuran and dioxane; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and hexamethylphosphoric triamide; or mixtures thereof; preferably ethers or amides.
The reaction temperature is 0xc2x0 C. to 150xc2x0 C., preferably 20xc2x0 C. to 100xc2x0 C.
While the reaction time varies depending on the reagent, the reaction temperature and the solvent, it is usually 1 hour to 3 days, preferably 1 hour to 24 hours.
Step B5
Step B5 is to prepare a compound of formula (IIa) and is carried out by converting the azide group of the compound of formula (IX) to an amino group.
The present reaction is accomplished by carrying out a catalytic reduction using palladium on carbon, Raney nickel, Lindlar catalyst, etc. as a catalyst or a reduction using triphenylphosphine, etc. in an inert solvent.
The solvent employed here is not particularly limited so long as it has no adverse effect on the present reaction and includes, for example, hydrocarbons such as benzene, toluene, xylene, hexane and heptane; alcohols such as methanol and ethanol; ethers such as diethyl ether, tetrahydrofuran and dioxane; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and hexamethylphosphoric triamide; and mixtures thereof; preferably alcohols or ethers.
The reaction temperature is 0xc2x0 C. to 150xc2x0 C., preferably 20xc2x0 C. to 100xc2x0 C. While the reaction time varies depending on the reagent, the reaction temperature and the solvent, it is usually 1 hour to 3 days, preferably 1 hour to 24 hours. 
wherein
R2, R3, R4, U, X, Y, W1 and M have the same meanings as defined above;
R7 represents a hydrogen atom; R8 represents an amino protecting group; or R7 and R8 each represent an amino protecting group; or R7, together with R8 represent an amino protecting group.
The amino protecting group of R7 or R8 is a protecting group well-known in organic synthetic chemistry and includes, for example, a C7-C14 aralkyl group such as benzyl, diphenylmethyl and trityl; a C1-C4 aliphatic acyl group which may be substituted with fluorine such as formyl and trifluoroacetyl; a C1-C4 alkoxycarbonyl group such as t-butoxycarbonyl; a benzyloxycarbonyl group which may be substituted with methoxy or nitro such as benzyloxycarbonyl, p-methoxybenzyloxycarbonyl or p-nitrobenzyloxycarbonyl. In the case where R7, together with R8 represent an amino protecting group, the protecting group includes, for example, a phthaloyl group, etc.; preferably a t-butoxycarbonyl, benzyloxycarbonyl or phthaloyl group.
Step C1
Step C1 is to prepare a compound of formula (XI) and is carried out by reacting a compound of formula (X) with a compound of formula (V).
The present step is carried out in a similar manner to that described in Step B1 of Method B.
Step C2
Step C2 is to prepare a compound of formula (IIa) and is carried out by removal of the amino protecting group from the compound of formula (XI).
In the case where the protecting group R7 or R8 is a group which can be removed by catalytic reduction such as an aralkyl group and an aralkyloxycarbonyl group or a group which can be removed using an acid such as a trityl group and a t-butoxycarbonyl group, the deprotecting reation is carried out in a similar manner to that described in Step A2 of Process A.
In the case where the protecting group R7 or R8 is an aliphatic acyl group such as formyl and trifluoroacetyl, the protecting group is removed under basic conditions.
The base employed here includes alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and lithium hydroxide; and alkali metal carbonates such as sodium carbonate and potassium carbonate; preferably alkali metal hydroxides.
The present reaction is preferably carried out in an inert solvent, for example, alcohols such as methanol and ethanol; water; ethers such as tetrahydrofuran and dioxane; and mixtures thereof; more preferably alcohols.
The reaction temperature is 0xc2x0 C. to 100xc2x0 C., preferably 10xc2x0 C. to 80xc2x0 C.
While the reaction time varies depending on the reagent, the reaction temperature and the solvent, it is usually 30 minutes to 24 hours, preferably 1 hour to 16 hours.
In the case where R7, together with R8 represent an amino protecting group and it is a phthaloyl group, the protecting group can be removed by treating it with hydrazines or primary amines.
The hydrazines employed here include, for example, hydrazine, methylhydrazine and phenylhydrazine, preferably hydrazine. The primary amines employed here includes methylamine, ethylamine, propylamine, butylamine, isobutylamine, pentylamine and hexylamine, preferably propylamine or butylamine.
In the present reaction, an inert solvent, for example, alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and dioxane; halogenated hydrocarbons such as methylene chloride and chloroform; and mixtures thereof are preferably used. The alcohols are more preferably employed.
The reaction temperature is 0xc2x0 C. to 100xc2x0 C., preferably 10xc2x0 C. to 80xc2x0 C.
While the reaction time varies depending on the reagent, the reaction temperature and the solvent, it is usually 30 minutes to 24 hours, preferably 1 hour to 16 hours.
In the formula (II) in Method A, a compound in which R1 is an alkyl group or an aralkyl group can also be prepared according to Method D or Method E. 
wherein R2, R3, R4, U1, Y, W1 and M have the same meanings as defined above. R1xe2x88x921 represents a straight or branched chain alkyl group having from 1 to 6 carbon atoms or an aralkyl group having from 7 to 12 carbon atoms.
Step D1
Step D1 is to prepare a compound of formula (IIb) and is carried out by reacting a compound of formula (VIII) with an amine of formula (XII).
The present reaction is carried out in an inert solvent in the presence or absence of a base.
The solvent employed here is not particularly limited so long as it has no adverse effect on the present reaction and includes,for example, hydrocarbons such as benzene, toluene, xylene, hexane and heptane; alcohols such as methanol and ethanol; ethers such as diethyl ether, tetrahydrofuran and dioxane; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and hexamethylphosphoric triamide; or mixtures thereof; preferably ethers or amides.
The base employed here includes alkali metal carbonates such as sodium carbonate and potassium carbonate; alkali metal hydrogencarbonates such as sodium hydrogencarbonate and potassium hydrogencarbonate; and tertiary organic amines such as triethylamine, N-methylmorpholine, N,N-diisopropylethylamine, 1,5-diazabicyclo[4.3.0]non-5-ene and 1,8-diazabicyclo[5.4.0]undec-7-ene; preferably alkali metal carbonates or tertiary organic amines.
The reaction temperature is 0xc2x0 C. to 150xc2x0 C., preferably 20xc2x0 C. to 100xc2x0 C.
While the reaction time varies depending on the reagent, the reaction temperature and the solvent, it is usually 1 hour to 3 days, preferably 1 hour to 24 hours. 
wherein
R1xe2x88x921, R2, R3, R4, Y, Z, W1 and M have the same meanings as defined above.
R9 represents a straight or branched chain alkyl group having from 1 to 6 carbon atoms or an aralkyl group having from 7 to 12 carbon atoms and R10 represents a straight or branched chain alkyl group having from 1 to 6 carbon atoms, an aralkyl group having from 7 to 12 carbon atoms or a hydrogen atom.
Step E1
Step E1 is to prepare a compound of formula (IIb) and is carried out by reacting a compound of formula (IIa) with a carbonyl compound of formula (XIII).
The present reaction is carried out in an inert solvent under reduction conditions using a metal hydride such as sodium borohydride and sodium cyanoborohydride or under catalytic reduction conditions using palladium on carbon or Raney nickel as a catalyst.
The solvent employed here is not particularly limited so long as it has no adverse effect on the present reaction and includes hydrocarbons such as benzene, toluene, xylene, hexane and heptane; alcohols such as methanol and ethanol; ethers such as diethyl ether, tetrahydrofuran and dioxane; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and hexamethylphosphoric triamide; or mixtures thereof; preferably alcohols or amides.
The reaction temperature is 0xc2x0 C. to 150xc2x0 C., preferably 20xc2x0 C. to 100xc2x0 C.
While the reaction time varies depending on the reagent, the reaction temperature and the solvent, it is usually 1 hour to 3 days, preferably 1 hour to 24 hours.
In the formula (III) in Method A, the compound (IIIa) in which W is an aryloxy group, a hetero aryloxy group, an arylthio group or a hetero arylthio group can be also prepared according to Method F. 
wherein R1, R2, R3, R4, U, X, Y, Z and M have the same meanings as defined above. W2 represents an aryloxy group, an hetero aryl group, an arylthio group or an hetero arylthio group in W described above.
Step F1
Step F1 in Method F is to prepare a compound of formula (IIIa) and the compound is prepared by reacting a compound of formula (XIV) with a compound of formula (XV).
The present step is carried out in a similar manner to that described in Step B1 of Process B.
In the formula (XI) in Method C, the compound (XIa) in which W is an aryloxy group, a hetero aryloxy group, an arylthio group or a hetero arylthio group can be also prepared according to Method G. 
wherein R2, R3, R4, R7, R8, U, W2, Y, Z and M have the same meanings as defined above.
Step G1
Step G1 in Method G is to prepare a compound of formula (XIa) and the compound is prepared by reacting a compound of formula (XVI) with a compound of formula (XV).
The present step is carried out in a similar manner to that described in Step B1 of Process B.
In the formula (I) in Method A, a compound (Ia) in which R4 is a hydrogen atom can be also prepared according to Method H. 
wherein R1, R2, R3, U1, W, W1, Y, Z and M have the same meanings as defined above.
Step H1
Step H1 in Method H is to prepare a compound of formula (XIX) and the compound is prepared by reacting a compound of formula (XVII) with a compound of formula (XVIII).
The present reaction is carried out by reacting the compounds in an inert solvent in the presence of a base.
The base employed here preferably includes alkali metal hydrides such as sodium hydride, potassium hydride and lithium hydride; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide and lithium methoxide; alkyl lithiums such as butyl lithium and methyl lithium; lithium amides such as lithium diethylamide, lithium diisopropylamide and lithium bis(trimethylsilyl)amide; or tertiary organic amines such as 1,5-diazabicyclo[4.3.0]non-5-ene and 1,8-diazabicyclo[5.4.0]undec-7-ene; more preferably alkali metal hydrides, alkali metal alkoxides or lithium amides.
The inert solvent employed in the reaction is not particularly limited so long as it has no adverse effect on the reaction and includes, for example, hydrocarbons such as benzene and toluene; ethers such as tetrahydrofuran and dioxane; alcohols such as methanol, ethanol and t-butanol; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidinone; ketones such as acetone and 2-butanone; nitrites such as acetonitrile; sulfoxides such as dimethyl sulfoxide; and mixtures thereof; preferably ethers, amides, ketones or sulfoxides.
In the case where the present reaction is carried out in the presence of a phase transfer catalyst such as benzyltriethylammonium iodide and tetrabutylammonium iodide, the present reaction is carried out in a two-layer solvent system of water and a halogenated hydrocarbon such as methylene chloride and chloroform using an alkali metal hydroxide such as sodium hydroxide and potassium hydroxide as the base.
The reaction temperature is xe2x88x9210xc2x0 C. to 120xc2x0 C., preferably 10xc2x0 C. to 100xc2x0 C.
While the reaction time varies depending on the reagent used and the reaction temperature, it is usually 30 minutes to 48 hours, preferably 1 hour to 16 hours.
Step H2
Step H2 is to prepare a phenylalkylcarboxylic acid derivative of formula (Ia) and is carried out by removal of the ester residues of the malonic acid diester derivative of formula (XIX), and then by decarboxylation.
The removal of the ester residue in the present step is accomplished by carrying out it in a similar manner to that described in Step A2 of Method A.
The step of decarboxylation is accomplished by heating the malonic acid derivative produced by removal of the ester residues of the compound of formula (XIX) in the presence of a solvent.
The solvent employed in the present step is not particularly limited so long as it has no adverse effect on the reaction and includes, for example, hydrocarbons such as benzene, toluene, xylene and heptane; halogenated hydrocarbons such as chloroform and carbon tetrachloride; ethers such as tetrahydrofuran and dioxane; alcohols such as ethanol, propanol, methoxyethanol and ethylene glycol; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and hexamethylphosphoric triamide; and mixtures thereof; preferably hydrocarbons or alcohols.
The reaction temperature is 60xc2x0 C. to 180xc2x0 C., preferably 80xc2x0 C. to 150xc2x0 C.
While the reaction time varies depending on the reagent, the reaction temperature and the solvent, it is usually 30 minutes to 2 days, preferably 1 hour to 24 hours.
In the formula (I) of Method A, a compound (Ib) in which W is an alkylamino group, a dialkylamino group or an aralkylamino group can be also prepared according to Method I. 
wherein R1, R2, R3, R4, X, Y, Z and M have the same meanings as defined above. W3 represents a straight or branched chain monoalkylamino group having from 1 to 4 carbon atoms, a straight or branched chain dialkylamino group in which each alkyl group may be the same or different and each has from 1 to 4 carbon atoms or an aralkylamino group having from 7 to 12 carbon atoms.
Step I1
Step I1 is to prepare a compound of formula (IIIc) and is carried out by alkylation or aralkylation of a compound of formula (IIIb).
The present reaction is carried out in a similar manner to that described in Step B1 of Method B in the case where an alkyl halide, aralkyl halide, alkyl sulfonate or aralkyl sulfonate is used as an alkylation reagent.
In the case where the alkylation is reductively carried out using a carbonyl compound, it is carried out in a similar manner to that described in Step E1 of Method E.
Step I2
Step I2 is to prepare a compound of formula (Ib) and is carried out by removal of the ester residue of the compound of formula (IIIc).
The present step is carried out in a similar manner to that described in Step A2 of Method A.
The desired compound obtained by each step described above can be purified, if necessary, by conventional methods, for example, column chromatography, recrystallization and reprecipitation after the reaction. For example, the reaction mixture is appropriately neutralized, a solvent is added to the reaction mixture to extract it and the solvent is distilled off from the extract. The residue thus obtained is purified by subjecting it to column chromatography using silica gel to obtain the purified product of the desired compound.
The amidocarboxylic acid derivatives of formula (I), the pharmacologically acceptable salts thereof or the pharmacologically acceptable esters thereof have some excellent effects of lowering glucose, reducing lipid, ameliorating insulin resistance, alleviating inflammatory disease, immunoregulation, inhibiting aldose reductase, inhibiting 5-lipoxygenase, suppressing generation of lipid peroxide, activating PPAR and alleviating osteoporosis and are useful as preventive and/or therapeutic agents (particularly therapeutic agents) for diseases caused by insulin resistance such as diabetes mellitus, hyperlipemia, obesity, impaired glucose torelance, insulin resistant non-impaired glucose torelance, hypertension, fatty liver, diabetic complications (e.g., retinopathy, nephropathy, neurosis, cataracts, coronary artery diseases, etc.), arteriosclerosis, gestational diabetes mellitus and polycystic ovary syndrome, cell injury induced by atherosclerosis and ischemic heart diseases (e.g., brain injury caused by apoplexy); inflammatory diseases such as arthrosteitis, pain, pyrexia, rheumatic arthritis, inflammatory enteritis, acne, sunburn, psoriasis, eczema, allergic diseases, asthma, GI ulcers, cancer, cachexia, autoimmune diseases and panceatitis; osteoporosis; and cataracts, etc.
The amidocarboxylic acid derivatives of formula (I) of the present invention, pharmacologically acceptable salts thereof or esters thereof are administered in various forms. The administration form is not particularly limited and is determined depending on various kinds of pharmaceutical formulation forms, age, sex and other conditions, the degree of disease of the patient, etc. For example, the compound may be orally administered, in the case of tablets, pills, powders, granules, syrups, solutions, suspensions, emulsions, granules and capsules. Meanwhile, in the case of injections, it is intravenously administered singly or in a mixture with a usual adjuvant solution such as glucose, an amino acid, etc. Furthermore, if necessary, it may be singly administered intramuscularly, intracutaneously, subcutaneously or intraperitoneally. In the case of suppositories, it is intrarectally administered. Oral administration is preferable. The various kinds of these pharmaceutical formulations can be prepared using known adjuvants usually used in the known pharmaceutical formulation field such as excipients, binders, disintegrators, lubricants, solubilizers, corrigents, and coating agents for a principal agent according to a conventional method.
When the present component is molded into the form of tablets, carriers known to one of ordinary skill in the art can be widely used, and includes excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose and silicic acid; binders such as water, ethanol, propanol, single syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate, and polyvinylpyrrolidone; disintegrators such as dry starch, sodium alginate, agar powder, laminaran powder, sodium hydrogencarbonate, calcium carbonate, polyoxyethylenesorbitan aliphatic acid ester, sodium lauryl sulfate, stearic acid monoglyceride, starch and lactose; disintegration inhibiting agents such as sucrose, stearic acid, cacao butter and hydrogenated oil; absorption accelerating agents such as a quaternary ammonium base and sodium lauryl sulfate; humectants such as glycerin and starch; adsorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid; and lubricants such as purified talc, a stearate, boric acid powder and polyethylene glycol. Further, the tablets can be made, if necessary, as tablets to which is applied a coating film, for example, a sugar coating tablet, a gelatin coating tablet, an enteric coated tablet, a film coating tablet, a double layer tablet or a multilayer tablet.
When the present compound is molded into the form of pills, carriers known to one of ordinary skill in the art can be widely used, and include, for example, excipients such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, kaolin and talc; binders such as gum Arabic powder, tragacanth powder, gelatin and ethanol; and disintegrants such as laminaran agar. When the present compound is molded into the form of suppositories, carriers known to one of ordinary skill in the art can be widely used, and include, for example, polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohol, gelatin and semi-synthetic glyceride.
In the case where the present compound is formulated as an injection, it is preferable that the solvents and suspending agents are sterilized and are isotonic to blood. When the present compound is formulated into such solutions, emulsions and suspensions, all diluents conventionally used in this field can be used, and include, for example, water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol and polyoxyethylenesorbitan aliphatic acid ester. Incidentally, in this case, a sufficient amount of NaCl, glucose or glycerin in order to prepare an isotonic solution may be contained in the pharmaceutical formulations. Further, conventional solubility improving agents, buffers and soothing agents may also be added thereto.
Further, colorants, preservatives, flavors, sweeteners and other pharmaceuticals may be contained therein, if necessary.
The amount of the active ingredient contained in the above-mentioned pharmaceutical formulations is not particulaly limited and is appropriately selected from a wide range, and it is preferable that the content is usually from 1 to 70% by weight in all compositions, more preferably from 1 to 30% by weight.
While the does will vary depending on the animal""s symptoms, age and body weight, and on the administration methods and form of the pharmaceutical formulations, it is usually administered in an amount of 0.000002 mg/kg (preferably 0.00002 mg/kg, more preferably 0.0002 mg/kg) as a lower limit and 40 mg/kg (preferably 4 mg/kg, more preferably 0.4 mg/kg) as an upper limit. For adult humans, it is usually administered in an amount of 0.0001 mg (preferably 0.001 mg, more preferably 0.01 mg) as a lower limit and 2000 mg (preferably 200 mg, more preferably 20 mg) as an upper limit from once to several times per day to an adult.